CHAPTER ELEVEN

Anti-cancer drug molecules

targeting cancer cell cycle
and proliferation
Debarun Patra, Kumari Bhavya, Palla Ramprasad, Moyna Kalia,
and Durba Pal*
Department of Biomedical Engineering, Indian Institute of Technology Ropar, Rupnagar, Punjab, India
*Corresponding author: e-mail address: [email protected]

Contents
1. Introduction 344
2. Overview of cell cycle checkpoints 348
3. Disturbance in cancer cell cycle checkpoints 351
4. Anti-cancer drugs 353
4.1 Historical perspective of anti-cancer drugs 353
4.2 Modern phase of anti-cancer drug development 355
5. Drugs that target cell cycle proteins 356
5.1 Targeting G1 phase regulatory proteins 356
5.2 S-phase targeted therapeutics 358
5.3 G2 and M phase inhibitors 368
5.4 Inhibitors of WEE1 and CHK1 kinases 369
5.5 Aurora kinase and polo kinase inhibitors 372
6. Cancer cell proliferation inhibitors 374
6.1 Hormone, hormone receptors, and cancer cell proliferation 378
7. Conclusion 380
References 382

Abstract
Cancer, a vicious clinical burden that potentiates maximum fatality for humankind, arises
due to unregulated excessive cell division and proliferation through an eccentric
expression of cell cycle regulator proteins. A set of evolutionarily conserved machinery
controls the cell cycle in an extremely precise manner so that a cell that went through
the cycle can produce a genetically identical copy. To achieve perfection, several check-
points were placed in the cycle for surveillance; so, errors during the division were rec-
tified by the repair strategies. However, irreparable damage leads to exit from the cell
cycle and induces programmed cell death. In comparison to a normal cell, cancer cells
facilitate the constitutive activation of many dormant proteins and impede negative
regulators of the checkpoint. Extensive studies in the last few decades on cell division

Advances in Protein Chemistry and Structural Biology, Volume 135 Copyright # 2023 Elsevier Inc. 343
ISSN 1876-1623 All rights reserved.
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344 Debarun Patra et al.

and proliferation of cancer cells elucidate the molecular mechanism of the cell-cycle
regulators that are often targeted for the development of anti-cancer therapy. Each
phase of the cell cycle has been regulated by a unique set of proteins including master
regulators Cyclins, and CDKs, along with the accessory proteins such as CKI, Cdc25,
error-responsive proteins, and various kinase proteins mainly WEE1 kinases, Polo-like
kinases, and Aurora kinases that control cell division. Here in this chapter, we have
analytically discussed the role of cell cycle regulators and proliferation factors in cancer
progression and the rationale of using various cell cycle-targeting drug molecules as
anti-cancer therapy.

Abbreviations
APC/C anaphase promoting complex/cyclosome
ATM ataxia-telangiectasia mutated
ATR ataxia telangiectasia and Rad3-related protein
BMP bone morphogenic proteins
BRAF B-rapidly accelerated fibrosarcoma
BuBR budding uninhibited by benzimidazole related
CDK cyclin-dependent kinases
CDt1 cdc10-dependent transcript 1 protein
CHK checkpoint kinase
CIN chromosomal instability
CIP CDK-interacting protein
CKI cyclin-dependent kinase inhibitors
CTLA-4 cytotoxic T-lymphocyte-associated antigen 4
DCC deleted in colorectal carcinoma
DDR DNA damage response
DPC deleted in pancreatic carcinoma
EGFR epidermal growth factor receptor
FOXM1 Forkhead box protein M1
MCM minichromosome maintenance protein complex
MYT1 myelin transcription factor 1
PDGFR platelet-derived growth factor receptor
SAC spindle assembly checkpoint
SMAD suppressor of mothers against decapentaplegic
TGF transforming growth factor beta
TNBC triple-negative breast cancer

1. Introduction
The advent of cell theory stating new cells come from pre-existing
cells initiates the concept of cell division. Deeper revelations of the complex
regulation of cell division at the molecular level lead to the unfolding of the
Cell cycle targeted anti-cancer therapy 345

cell cycle event as a sequence of extremely organized and tightly controlled

phases that ensure the reproduction of the cell (Mazzarello, 1999). The cell
cycle has four distinct phases—G0/G1, S, G2, and M with sets of macromo-
lecular assembly. Studies using micro-spectrophotometry (Swift, 1950)
and autoradiography (Howard & Pelc, 1953) in eukaryotic cells revealed
that DNA replication occurs in the S phase and mitotic/meiotic division
taking place in M phase, with the preparatory gap phases before and
after S phase are as G1 and G2, respectively (Sisken, 1972).
In the G1 phase (pre-synthetic phase), due to the synthesis of ribonucleic
acid (RNA), and protein along with the development of new organelles, the
cell becomes doubles in size by the transition end of the G1 phase. Whereas
in the S phase (synthetic phase), cell doubles its DNA content and produces
RNA and proteins, forming a duplicate copy of each chromosome (Wang,
2021). In the G2 phase (premitotic phase), the cell prepares for mitosis
as DNA synthesis ceases but RNA and protein synthesis continue
(Lockhead et al., 2020). Finally, in the M Phase (mitosis) the cell divides into
two daughter cells as a result of nuclear and cytoplasmic division, with an
identical quantity of genetic material similar to the parent cell. The decision
for cell division has been made based on internal and external cues. Internal
signals can act as “stop signals,” such as cells with insufficient food supply,
poor DNA synthesis, and inefficient kinetochore attachment. On the other
hand, a “start signal” combines high levels of cyclin, a steady level of
mitosis-promoting factor (MPF), completed DNA replication, and attach-
ment of all sister chromatids to kinetochore spindle fibers. Similar to internal
signals, external “stop signals” include factors like inadequate growing
space and improper anchoring, whereas the availability of growth factors
and hormones can play as a “start signal.” The regulation of the cell cycle
is critically maintained by cyclin-dependent kinases (CDKs) interacting
with specific partner proteins, Cyclins; altogether safeguarding the cell divi-
sion at several checkpoints. Dysfunction at any phase leads to an uncon-
trolled cell cycle that leads to the development of cancer which is mainly
associated with alterations in CDK activity. Dysregulated CDKs bring
unscheduled proliferation as well as genomic and chromosomal instability
(Dominguez-Brauer et al., 2015).
Uncontrolled cell division necessitates abnormal mitogenic signaling,
which is fuelled by either excessive external signaling (such as growth
factors and nutrition) or endogenous oncogenic mutations. It is also influen-
ced by mutations that alter mitogenic breaks (such as tumor suppressors
and negative regulators), and lower the threshold for mitogenic signaling
346 Debarun Patra et al.

(Feitelson et al., 2015). The cyclin/CDKs complex is negatively regulated

by cyclin-dependent kinase inhibitors (CKIs), such as the inhibitor of
CDK4 (INK4) proteins (p16INK4a, p15INK4b, p18INK4c, and p19INK4d),
and CDK-interacting protein/kinase inhibitory proteins (CIP/KIPs)
(p21CIP1, p27KIP1, and p57Kip2) (Asghar, Witkiewicz, Turner, & Knudsen,
2015). CDKs act as the catalytic subunits by forming a heterodimer complex
with the cyclins, which function as the regulatory subunits. Reportedly,
human cells have 20 CDKs and 29 cyclins; among them, CDK1–7 directly
regulates cell-cycle transitions and CDK7, 8, 9, 11, and 20 mediate
mRNA synthesis (Ding et al., 2020). Mitogenic stimulation activates signal-
ing pathways and impinges on cyclin D-CDK4/6 for their subsequent
activation to initiate phosphorylation and inactivation of the tumor suppres-
sor Retinoblastoma (Rb) protein early in the G1 phase (Knudsen &
Witkiewicz, 2017). The G1/S checkpoint detects the stress on DNA repli-
cation brought on by the oncogene. Increased mutation rates cause the fail-
ure of the regulatory mechanism, which could eventually cause genomic
instability. Defects in the spindle assembly checkpoint during mitosis lead
to a dysregulation of CDK1 activity, which may lead to aberrant chromo-
somal segregation. All of these flaws combine to cause inappropriate
CDK activity, which inevitably results in the development and growth of
tumors (Casimiro, Crosariol, Loro, Li, & Pestell, 2012). Fig. 1 showed
certain mutations in the cell cycle that induces cancer.
Existing radio- or chemo-therapeutic modalities cause excessive DNA
damage in cancer cells and so more likely to cause catastrophic levels of
genome instability that result in death of cancer cells as well as healthy
cells. Other therapeutic interventions include forcing the cancer cells to per-
manently exit from the cell cycle. Since enhanced CDK activity has been
frequently reported in a variety of malignancies, thus CDKs are appealing
targets for novel therapies against cancers. The cell cycle progression can
be postponed or arrested using CDK inhibitors as targets until particular
conditions are met. Because cancer cells are more dependent on a spindle
assembly checkpoint (SAC) compared to a normal cell, thus cancer cells
drive catastrophic chromosomal instability (CIN) to avoid mistakes during
the M phase (Levine & Holland, 2018; Wilhelm, Said, & Naim, 2020).
These methods have the potential to use in individuals or with currently
available medications that cause DNA damage and replication stress.
Recent advancements in pertinent to cell cycle regulation and cancer pro-
gression help us to develop advanced therapies and also open up therapeutic
opportunities to enhance initial treatment with curative intent, either
Cell cycle targeted anti-cancer therapy 347

Fig. 1 Cell cycle phase transitions are carried out by a complex interplay of various sig-
naling pathways and regulatory proteins. During G1 phase, mitogenic signals (various
growth factors like EGF, TGF) can induce cyclin D activation through stimulation of
proto-oncogenes. This further leads to the formation of active cyclin D-CDK4/6 com-
plexes which are inhibited by the INK4A-D set of proteins. Cyclin D-CDK4/6 complexes
drive phosphorylation (p) of the retinoblastoma (RB) protein. Several S phase-promoting
genes, including cyclin E (CCNE1, CCNE2), CDC6, CDC7, CDK2, CDK1, MCM, and DBF4 are
activated by the release of E2F transcription factors from RB hyperphosphorylation.
In response to growth-inhibitory signals inhibitory proteins p27KIP1 and p21CIP1 interact
with cyclin E-CDK2 complex to maintain an inactive state. APC/C-CDH1 inhibited by
Cyclin E/CDK2 complex at the end of G1 phase that was known to preserve low levels
of mitotic and S phase cyclins in G1 phase. The DBF4–CDC7 complex is required for
initiating replication during the G1-S phase transition. The cyclin E-CDK2 complex is
kept in a dormant state through ubiquitination by protein complex SCF7-FBXW7.
Activation of cyclin E-CDK2 complex leads to replication fork progression. In the S phase
DNA replication machinery is phosphorylated and activated by cyclin A-CDK2 for
the completion of DNA synthesis. Cyclin A activates cyclin B-CDK1 during the G2
phase. In this phase forkhead box M1 (FOXM1) transcription factor connects with the
MUVB complex and leads to induction of CCNA2, CCNB1, CCNB, CDC25, PLK1, and AURK
(Continued)
348 Debarun Patra et al.

through increased precision or by extending therapeutic modalities and

better-informed treatment decisions that will improve patient outcomes.
In this chapter, we summarize all such cell cycle proteins that get dys-
regulated at the onset of cancer and the development of targeted inhibitors
as novel therapeutic interventions for cancer treatment.

2. Overview of cell cycle checkpoints

Cell cycle checkpoints are regulatory processes that keep an eye on the
consistency, dependability, and order of the basic cell cycle events. These
include DNA replication and repair, chromosomal integrity, maintenance
of cell size and functions and appropriate chromosome segregation during
mitosis (Barnum & O’Connell, 2014; Mar
echal & Zou, 2013). These cell
cycle events are tightly regulated through which cellular components are
duplicated and divided into two identical daughter cells. The assembling
of certain macromolecules constitutes the machinery that is crucial for
driving each cell-cycle event. For instance, protein “machines” that create
the replication origins and forks necessary for DNA duplication during the S
phase take place “only once” during a cell cycle to preserve the genome
(O’Donnell, Langston, & Stillman, 2013). The re-replication from a single
origin might result in aneuploidy and DNA damage, and therefore, it is
crucial to prevent re-initiation from an origin when replication has already
been completed in a particular cell cycle (Blow & Dutta, 2005; Truong &
Wu, 2011).
At the very initial phase of the cell cycle, the G1 checkpoint assures
that all circumstances are ideal for cell division to continue. External stimuli,
like growth factors, significantly impacted the decision for the onset and

Fig. 1—Cont’d facilitating entry and progressing through mitosis (M phase). The
cyclin H-CDK7 complex, also known as the CDK-activating kinase (CAK), phosphorylates
CDK1 to activate cyclin B/CDK1 kinase. The protein kinases membrane-associated
cdc2-inhibitory kinase (MYT1) and WEE1 are responsible for the inhibitory Thr14 and
Tyr15 phosphorylations, respectively. CDK1 activation is suppressed in response
to G2 DNA damage checkpoint activation through checkpoint kinase 1 (CHK1).
Following the repair of DNA damage, polo-like kinase 1 (PLK1) is necessary for reac-
tivation of CDK1. Cyclin A/B-CDK1 complexes must be activated sufficiently to begin
mitosis. During nuclear envelope disintegration in mitosis, cyclin A is broken down
by APC/C-CDC20. APC/C-CDC20 further causes degradation of cyclin B and securin,
which is responsible for chromosome segregation. APC/C-CDH1 activity resumes in
anaphase, when it regulates the stability of mitotic factors like Aurora A and PLK1,
and continues throughout the following G1 phase.
Cell cycle targeted anti-cancer therapy 349

progression of the cell cycle (Blagosklonny & Pardee, 2000-2013). At the

G1 checkpoint (also known as start or restriction checkpoints), there is
an inspection for genomic DNA damage in addition to sufficient reserves
and cell size. A cell won’t be permitted to enter into the S phase if it
doesn’t match all the prerequisite parameters. The cell has two options: it
can stop the cycle and try to fix the issue (Repairing), or it can go into
the G0 phase and wait for specific signals when the situation becomes better
(Blagosklonny & Pardee, 2000-2013). The ATM(ATR)/CHK2(CHK1)-
p53/MDM2-p21 pathway is the predominant checkpoint responder to
DNA damage mainly in mammalian cells transitioning through G1, and
it can induce prolonged, and occasionally even, irreversible G1 arrest.
The expression levels of ATR and CHK1 are minimal in early-to-mid
G1, however, their actions are prominent at the G1/S transition, whereas
ATM and CHK2 expression are rather stable throughout the G1 phase of
the cell cycle. DNA damage-associated activation of ATM/ATR kinases
can directly phosphorylate d the Ser15 residue of the amino-terminal
transactivation domain of the p53 transcription factor that facilitates its sep-
aration from the negative regulator Mdm2 and activates p53 transactivation
potential. CHK1/CHK2 also targets the same domain but on Thr18 and
Ser20 residues, as well as on some other p53 sequences (Kastan & Bartek,
2004). The activated p53 acts as a transcription factor and regulates the
expression of p21 and Mdm2. p21cip1/waf1, the primary transcriptional target
of p53, silences the G1/S-phase cyclin E/Cdk2 and thus results in G1/S
arrest. In addition, p21 also targets cyclin D-CDK4/6 in the G1 phase
preventing pRB activation and E2F separation keeping RB/E2F pathway
in check resulting in G1 checkpoint blockage. p53 and pRB are indeed
the most critical regulators of the cell cycle and their dysregulated processes
occur frequently in human cancer (Daud et al., 2015; Kastan & Bartek, 2004;
Sakurikar & Eastman, 2015). In abnormal conditions, ATR and CHK1
expression elevates in late G1 as a result of the enhanced E2F-dependent,
S-phase-promoting transcriptional pathway. By the end of G1, cyclins E
and A as well as the Cdc25A phosphatase activate cyclin E/A/CDK2 kinases
(Bartek & Lukas, 2003; Bartek, Lukas, & Lukas, 2004). If the p53-dependent
mechanism prolongs the G1 arrest, the CHK1/CHK2-Cdc25A check-
point merely delays the G1/S transition for a few hours and implements
the p53-independent pathway (Kastan & Bartek, 2004).
The process of DNA synthesis is temporally divided into two steps:
origin licensing in the G1 phase and replication initiation (also known as
“origin firing”) in the S phase (Matthews, Bertoli, & de Bruin, 2022).
350 Debarun Patra et al.

Cells return to interphase with reduced CDK activity after a cell division
cycle is completed. Lack of CDK activity enables the inactive MCM helicase
complex to load onto replication origins under the control of Cdc6 and
CDt1, thus “licensing” all the origins (Hernández-Carralero et al., 2018).
The S-phase checkpoint is a regulatory mechanism that reacts to replicative
DNA damage by coordinating a thorough cellular response necessary to
preserve genomic integrity. Specific cell cycle checkpoints interrupt or
slow down the cell cycle in response to DNA damage during interphase,
replication stress during the S phase, or inadequate spindle assembly during
the M phase (Iyer & Rhind, 2017).
Double-strand DNA breaks (DsBs) in interphase potentially trigger the
DNA damage checkpoint, which depends on the protein kinases ATM and
CHK2 to stop cell cycle progression (Mar
echal & Zou, 2013). It can either
impede the accumulation of cyclin E/A-CDK2 activity by degrading
Cdc25A to cause momentary blockage of replication starting in the pre-S
phase or block mitotic entrance during the S phase and G2 phase, depending
on the cell cycle stage (Ding et al., 2020). When single-stranded DNA is
present, the replication stress checkpoint is triggered as the checkpoint
protein kinases ATR and CHK1 act to prevent the build-up of cyclin
A/B-CDK1/2 activity, which would otherwise inhibit mitotic entry
(Zhu, Swami, Preet, & Zhang, 2020). Activation of the WEE1 kinase along
with inhibition of the Cdc25 phosphatase induces CDK1/2 phosphory-
lation in an inhibitory manner and critically controls the downstream
regulation (Sur & Agrawal, 2016).
Like G1, G2 is again a gap phase where protein storage and cell size are
evaluated. The G2/M checkpoint prevents the cell’s entry into the M phase.
This checkpoint’s primary responsibility is to make sure that each of the
chromosomes has already been duplicated and that the replicated DNA
has not been damaged or mutated. The cell cycle is stopped if the G2 check-
point mechanisms identify DNA abnormalities, and the cell then tries to
fix the defective DNA. The inactivation of Cdc25 by posttranslational
modification—is the main cause of G2 arrest induction. Stable G2 arrest
contributes to genome protection and tumor suppression by inhibiting
erroneous entrance into mitosis (Stark & Taylor, 2004).
A distinctive failsafe mechanism called the mitotic checkpoint ensures
accurate chromosomal segregation. The Anaphase Promoting Complex/
Cyclosome (APC/C) is a multi-subunit E3 ubiquitin ligase that primarily
governs sister-chromatid segregation and mitotic progression. APC/C
comprised approximately 14 core subunits and recruits its substrates for
Cell cycle targeted anti-cancer therapy 351

ubiquitination via two adaptor proteins, either Cdc20 or Cdh1. Cdc20 (cell-
division-cycle 20 homologs) is known as a specificity factor for APC/C
activity to locate and engage with mitotic substrates. APC/C specifically
targets two proteins; Securin34 and cyclin B1, which are known as the
“master regulator” of mitosis, for destruction (Peters, 2002). The cohesin
connections that hold the sister chromatids together are broken by separase
when securin is degraded. However, the degradation of cyclin B1 results
in CDK1’s inactivation and starts the mitotic exit process (Kops,
Weaver, & Cleveland, 2005). APC/C is inhibited by the mitotic checkpoint
complex (MCC) due to checkpoint signaling, which is caused by faulty
kinetochore-microtubule contacts (Liu & Zhang, 2016). In the majority
of the species examined, the MCC has the following four components as
its effector: BuBR1, BuB3, Cdc20, and MaD2. All four proteins are evolu-
tionarily conserved, but BuB3 is missing from the fission yeast MCC (Chao,
Kulkarni, Zhang, Kong, & Barford, 2012; Sczaniecka et al., 2008). The
mitotic checkpoint complex (MCC; BuB3 along with MaD2 and MaD3
bound to Cdc20 is necessary to suppress the activation of the spindle assem-
bly checkpoint, which is triggered by incomplete attachment of chromo-
somes to the mitotic spindle (Fig. 1) (Arias & Walter, 2007; Matthews
et al., 2022; Stillman, 1996). Spindle Assembly Checkpoint (SAC) also
known as the mitotic checkpoint, a protective mechanism of mitosis that
avoids mistakes in chromosomal separation by delaying entry into anaphase
until mitotic spindle assembly is complete ensuring accurate separation of
the duplicated genome.

3. Disturbance in cancer cell cycle checkpoints

Cell cycle checkpoints often go wrong leading to tumorigenesis.
Reversible quiescence can cause a cell to exit the cell cycle, and senescence
or apoptosis causes a cell to exit the cell cycle irreversibly. The DNA damage
checkpoint determines whether or not to halt the cell cycle and repair
the damage, and it can proceed toward quiescence, senescence, or
programmed cell death. Interestingly, the most frequent mutations discov-
ered in many cancer types are p53 mutations (Gasco, Shami, & Crook,
2002). These mutations promote cells’ entry into the S phase and impair
cell’s capacity to exit the cell cycle in the pre-replicative phase by inducing
E2F-dependent transcription (Massagu
e, 2004). Importantly, the G2
checkpoint and the spindle assembly checkpoint are not typically altered
in cancer cells because their primary roles are crucial for them to proliferate
352 Debarun Patra et al.

(Malumbres & Barbacid, 2009). It is believed that due to replication stress,

also known as oncogene-induced replication stress, it quickening the cells’
entry into the S phase. The human papillomavirus E7 oncoprotein extends
the activation of MYC and cyclin E-CDK2, or loss of Rb ultimately stim-
ulates E2F-dependent transcription that has been connected to aberrant
replication initiation (Malumbres & Barbacid, 2009). Replication stress
has been linked to chromosomal instability (CIN) in certain circumstances.
Cancer cells, where constant replication stress occurs, are more dependent
on the replication stress checkpoint in response to catastrophic amounts of
replication stress-induced DNA damage. Indeed, all cell types including
cancer cells critically dependent on the kinases ATR and CHK1 for their
survival by propelling through sheer replication stress. It also shows added
dependency on the SAC due to oncogene-induced replication stress.
Cancer patients frequently exhibit aneuploidy, due to severe mitotic mis-
takes that can result in aberrant chromosomal arrangements. A faulty
SAC would be an obvious cause of faulty chromosomal segregation. SAC
gene mutations have been identified in cancer, although they are uncom-
mon (Gordon, Resio, & Pellman, 2012). But frequent mRNA over-
expression of SAC components (such as MPS1, MaD1, MaD2, BuBR1,
and Cdc20) has been observed in many cancer types (Sarkar et al., 2021).
Although, SAC malfunction is not solely responsible for its contribution
to carcinogenesis rather it can be stated cancer cells rely on the SAC more
than healthy cells do. The complete removal of the SAC in cancer cells is
always fatal due to catastrophic chromosomal loss. On the other hand,
non-transformed cells are less vulnerable to SAC inhibition-induced cell
death. Compared to normal cells, cancer cell lines spend three to five times
longer in metaphase, which is probably due to persistent checkpoint
activation delaying mitotic departure. Taxanes (Paclitaxel, Docetaxel,
etc.) and vinca alkaloids (Vinblastine, Vincristine, etc.) are two most widely
used anti-cancer drugs that are known to activate SAC (Visconti, Della
Monica, & Grieco, 2016).
The existence of aneuploidy and continuous CIN-related karyotypic
alterations occurs in many cancer cells which results in the loss or gain of
entire chromosomes (numerical CIN) or the rearrangement of chromosome
regions (structural CIN) (Bach, Zhang, & Sood, 2019). Reportedly, repli-
cation stress during the S phase and DNA damage response activation during
mitosis is sources of CIN. Recent studies reveal that modest levels of CIN
are advantageous to cancer cells and promote the evolution of cancer by
expanding potential karyotypic combinations. On contrary, increasing
Cell cycle targeted anti-cancer therapy 353

CIN is damage-inducing by the loss of vital genes that inhibits growth

and causes cell death (Sarkar et al., 2021). Experimental CIN induction
in diploid cells causes a decline in APC/C-Cdc20 action, which lengthens
mitosis and prevents the recurrence of excessive CIN. Therefore, a larger
dependency on the mitotic checkpoint may be necessary for cancer cells
to survive aneuploidy (Geigl, Obenauf, Schwarzbraun, & Speicher,
2008). Thus, understanding cell cycle checkpoint regulations in cancer cells
holds crucial importance for developing novel anti-cancer therapeutics.

4. Anti-cancer drugs
4.1 Historical perspective of anti-cancer drugs
Cancer wasn’t understood as a disease with particular biological causes other
than those tied to supernatural occurrences like the outcome of esoteric
powers connected to the evil power of the ancient Egyptian Gods but
instead of physical or biological causes until 400 BC (Bryan & Smith,
1930; Kelly & Mahalingam, 2015). Hippocrates, for instance, was the first
“scientist” to describe cancer in terms of science. He believed that the tumor
was a condition brought on by an imbalance between the four main
body humor—blood, phlegm, yellow, and black bile and postulates the first
scientific theory on the causes of cancer that began when the body produced
too much black bile. He also classified tumors into three groups: hard
cancers, ulcerated cancers, and hidden cancers, labeling the latter as incurable
(Karpozilos & Pavlidis, 2004; Tsoucalas & Sgantzos, 2016).
The words on a papyrus discovered by Edwin Smith, which describes a
breast cancer case and the surgical procedure used, are the first historical and
scientific records of malignancies in humans around 3000 BC during the
Egyptian period (Breasted, 1930; Sanchez, 2014). Alessandro Carugo
et al., grouped hematology and oncology medications into three drug devel-
opment eras that distinguish the identification and creation of treatments in
response to the escalating complication of the discovery: Cytotoxic agents
in the Bronze Age, command-and-control systems in the Silver Age, and
the Golden Age (understanding complex biology). The scientific character-
ization of deadly cell morphologies using chemical agents, largely natural
chemicals concentrated during the Bronze Age of anticancer drug discovery.
The process of drug development was unstructured, and the majority of
discoveries were dispersed across various separate laboratories (Carugo &
Draetta, 2019).
354 Debarun Patra et al.

The first reference to documented cancer treatment was made in 1861 by

Robert Bentley of Kings College London, who spoke of an extract from the
roots of Podophyllum peltatum plant having a local antitumor effect ( Jones,
2014). The mechanism of tumor suppression was addressed when King
and Sullivan found that podophyllotoxin prevents the mitotic spindle for-
mation in dividing cells at metaphase in 1946. This discovery subsequently
served as the inspiration for the design and chemical synthesis of two
structural equivalents, etoposide, and teniposide, which were developed
at Sandoz in the late 1960s and early 1970s. It’s important to note that topo-
isomerase II, a critical DNA regulatory enzyme, can likewise be inhibited by
these two analogs. These two medications have been proven to be successful
in treating testicular, small-cell lung, leukemia, and lymphoma cancer
( Jones, 2014).
As opposed to the conventional chemotherapy approach, which kills
both normal cells and malignant cells, targeted therapy directly intervenes
on oncogenes or tumor suppressor genes engaged in the growth of tumors.
For the last few decades, scientists intending to discover specific drug
candidates that could promote the targeted killing of cancer cells without
poising any toxic effect on healthy cells. Finding such molecules has con-
stantly advanced over the last several decades from relying heavily on empir-
ical cell-based surveillance to analyse anti-proliferative events and shifting on
to greater target-based approaches. When studying chronic myelocytic
leukemia (CML), scientists at the NCI noticed abnormalities in one of
the chromosomes, which they eventually named the Philadelphia chromo-
some because it included a fusion gene known as BCR-ABL. The develop-
ment of BCR-ABL fusion in CML patients’ blood cells was demonstrated
by Owen Witte and his associates at the University of California, US.
Imatinib (Gleevec), formerly known as STI-571, a medication that was
remarkably effective at eliminating CML cells was discovered by Brian
Drucker and his colleagues from Oregon Health and Science Center. It
inhibits the BCR-ABL fusion protein’s function and therefore effectively
manages CML (Sacha, 2014). This approach of treating cancer patients with
completely changed the way cancer therapy was handled. Since then,
numerous medications, as well as strategies are developed for searching
for novel anticancer agents, such as targeted compounds, monoclonal anti-
bodies, and T cell-based therapeutics that were approved for the treatment
of different types of cancers (Sim, Dhar, Robertson, Zagnoni, &
Mulholland, 2018). The concept of “targeted therapy” now pertains to
all medical interventions involving particular molecular targets; this strategy
Cell cycle targeted anti-cancer therapy 355

makes use of either chemically synthesized small molecules or biological

drugs, recombinant proteins, and monoclonal antibodies, targeted at partic-
ular cellular receptors and proteins involved in malignant processes
(Tsimberidou, 2015).
Modern drug discovery has ushered in a major shift in our understanding
of human biology. With the help of advances in genetics, genomics, immu-
nology, and other fields, we have been able to establish the molecular cause
of disease and identify potential targets for drug discovery. To support the
use of targeted therapies in the context of anticancer drug discovery,
George K€ ohler and C
esar Milstein’s discoveries in 1975 paved the way
for the generation of a variety of specific hybrid monoclonal antibodies
that are specific to various tumor antigens or cellular targets (K€ ohler &
Milstein, 1975). Immuno-oncology has also been introduced clinically with
highly effective newer therapeutic approaches that have fundamentally
altered our understanding of the tumor microenvironment and the critical
role of non-cancer cells in tumor progression (Carugo & Draetta, 2019).

4.2 Modern phase of anti-cancer drug development

Advanced knowledge of tumor biology and its microenvironment helps us
to differentiate neoplastic cells from normal healthy cells. As a result, several
targeted compounds have been developed against tumor cells proliferation,
such as monoclonal antibodies (mAbs), small molecule inhibitors (SMIs),
interfering RNA (iRNA) molecules, and regulators of microRNAs
(Crisci et al., 2019). A few categories of contemporary medications can
be classified depending on their preferential activity against cancer cells
progression, including cytokine receptor blockers, intracellular kinase
inhibitors, transcription factor antagonists, cell cycle modulators, cell adhe-
sion inhibitors, and proteasome blockers ( Jolanta Natalia & Magdalena,
2013). Monoclonal antibodies or small-molecule medications make up
the majority of targeted therapy. Small-molecule medications are employed
to target the intracellular molecules because they can easily enter the cells
due to their small size. Monoclonal antibodies targeting cancer cells can
be conjugated with the toxin, cytokines, and pro-drugs or bispecific mono-
clonal antibodies can be developed that could both cancer and immune cell
types. For example, T cells are assisted in killing cancer cells by monoclonal
antibodies by bringing them near the cancer cells. Blincyto®, is a type of
antibody that interacts with both CD19, a protein on the surface of leukemia
cells, and CD3, a surface marker of T cells. This procedure aids the T cells in
356 Debarun Patra et al.

approaching the leukemia cells and their killing. T-cell immunological

activity is negatively regulated by immune checkpoints called programmed
death 1 (PD-1), which typically functions as a kind of “off switch” to prevent
the T cells from targeting neighboring bodily cells, and cytotoxic
T-lymphocyte-associated antigen 4 (CTLA-4) (Buchbinder & Desai,
2016). Novel therapeutic approaches for melanoma, non-small cell lung
cancer, and other cancers have been developed as a consequence of the block-
ade of these targets which boosted immune activation against cancers. A
CTLA-4 inhibitor, Ipilimumab, is approved to treat advanced melanomas.
Combined PD-1 inhibitors, nivolumab, and pembrolizumab, are authorized
to treat people with advanced metastatic melanoma and people with meta-
static resistant non-small cell lung cancer (Buchbinder & Desai, 2016;
Wojtukiewicz et al., 2021). For the treatment of different cancers, numerous
organizations have created anti-miR medicines targeting miR-21, miR-17,
miR-155, and miR-29. The term “epitranscriptome” refers to various
(more than 150) chemical alterations that RNA molecules can experience
in living cells that influence their longevity, processing, as well as other
post-transcriptional activities. 5-Methylcytidine (m5C), pseudouridine
(s2U), N6-methyladenosine (m6A), inosine, N7-methylguanosine (m7G)
and several 20 -O-methylated nucleosides are few of the frequently altered
mRNA nucleosides. Each chemical change has a distinct function, such
as m6A’s enhancement of mRNA turnover regulates bone metastasis in
prostate cancer (Khan et al., 2021). Antisense oligos which target the endog-
enous retroviruses long terminal repeats (ERV-9 LTR) RNAs, demon-
strated that its delivery can limit the growth of cancer cells in vitro more
effectively than the antisense oligos of Bcl-2 (G3139) and telomerase
(GRN163), both of which are presently being tested in cancer clinical trials
(Kwok et al., 2017; Ors-Kumoglu, Gulce-Iz, & Biray-Avci, 2019; Xu,
Rosenberg, Elkahloun, & Candotti, 2020).

5. Drugs that target cell cycle proteins

5.1 Targeting G1 phase regulatory proteins
In mammalian cells, the G1 is the most critical phase of the cell cycle
where the cell fate decision is determined either to proceed for division
or exit from the cell cycle. Due to unfavorable growth conditions or inhib-
itory signals, cells may stay for longer periods in the G1 phase or even enter
into a prolonged non-dividing state, often known as the G0 phase (Bertoli,
Skotheim, & de Bruin, 2013). Although most adult tissues are maintained in
Cell cycle targeted anti-cancer therapy 357

a quiescent (G0) state, however, the activation of certain signaling pathways

including the mitogen-activated protein kinase (MAPK) pathway the Janus
kinase/signal transducer and activator of transcription (JAK-STAT) path-
way, Phosphatidylinositol 3-kinase/Akt or protein kinase B (PI3K-AKT)
pathway by the growth factors or hormonal stimulation leads to the
stimulation of cyclin D which binds to the CDK4/6 for their subsequent
phosphorylation of the tumor suppressor protein Retinoblastoma (Rb)
allows cell progression in G1 phase (Shields, Court, Hauser, Bukczynska,
& Tiganis, 2008). Phosphorylation of protein Rb causes its inactivation
and release of the E2F transcription factor, which in turn results in the
transcription of the E2F-responsive genes required for cell cycle progression.
In the late G1 phase, CDK2/Cyclin E active complex completes the
hyper-phosphorylation of Rb, leading cells to override the restriction point
at the boundary of the G1/S phase, resulting in S-phase initiation. A plethora
of anti-cancer drugs have been discovered and few are in pipeline that targets
G1 checkpoint proteins and their regulators (Giacinti & Giordano, 2006).
Palbociclib (Ibrance) is a selective inhibitor of CDKs 4/6 and was
developed by scientists from Pfizer, Ann Arbor, Michigan, with research
collaboration with Onyx Pharmaceuticals (McCain, 2015; Schmidt,
2016). Palbociclib completely suppresses the CDK4/6-cyclinD1 mediated
phosphorylation of pRB at Ser780/Ser795 and leads to a cell cycle block
in G1 in multiple myeloma cells. Palbociclib causes the elimination of
pRb and Ki67, as observed in the immunohistochemical analysis (Piezzo
et al., 2020). Palbociclib is available in the market in the form of coated tablet
with the brand name Ibrance; however, the major side effect is neutropenia
(low count of neutrophils in blood than normal).
Ribociclib (LEE011) is a bioavailable selective inhibitor of CDK4/6
which was discovered by the Novartis Institute for Biomedical Research
in collaboration with Astex Pharmaceuticals (Infante et al., 2016).
Ribociclib (Kisquali) was first approved by the US FDA for the treatment
of hormone receptor-positive (HR+)/human epidermal growth factor 2
negative (HER2) advanced breast cancer (RB-positive advanced solid
tumors) and lymphomas (Tripathy, Bardia, & Sellers, 2017). The clinical
impact and mechanism of action of Ribociclib showed that it inhibits the
growth of the majority of pRb-positive breast cancer cells with IC50 values
<1 μM (Adon, Shanmugarajan, & Kumar, 2021). In vitro, Ribociclib
caused cell-cycle arrest and cellular senescence with reduced phosphoryla-
tion of the Rb protein and the transcription factor FOXM1 (forkhead
box protein M1) (Hamilton & Infante, 2016). Various scientific studies
358 Debarun Patra et al.

reported the clinical trial of Ribociclib along with letrozole, goserelin/

leuprolide, where patients receive Ribociclib (orally 3 weeks on/1 week
off ) in combination with letrozole (orally taken once daily) (Campone
et al., 2022; De Laurentiis et al., 2021; Salvador Bofill et al., 2022).
Abemaciclib (Verzenio), a reversible ATP-competitive CDK4/6 inhib-
itor developed by Eli Lilly and Company, was approved by the US FDA in
2017 for ER-positive, HER2-negative metastatic breast cancer (Eli Lilly and
Company, 2021). Abemaciclib can promote human T-cell activation by
upregulating the expression of antigen-presenting genes in breast cancer cells
and increase T-cell inflammation that resulted in tumor growth delay.
Moreover, Abemaciclib along with anti-PDL1 antibodies can induce
immunological memory and tumor elimination. Therefore, combination
therapy presents great potential in clinical application for cancer treatment
(Schaer et al., 2018).
The first example of a covalent inhibitor of CDK, SY-136585 was
entered into clinical trials in 2017. Despite the initial reports of ATP-
non-competitive inhibitors, progress in this area has been lagging. Initial
examples of CDK-targeted protein degradation with small molecule
PROTACS88–99 or antibody-drug conjugates (ADC) have been recently
reported (Olson et al., 2018; Robb et al., 2017). Iksuda Therapeutics is
developing the first CDK11-based ADC and intends to identify this year
for its first clinical candidate. Both strategies represent an exciting and
emerging approach for CDK inhibition and could provide a greater under-
standing of CDK roles beyond the cell cycle and transcription. Among
researchers, CDK4/6 has consistently been a hot topic as targeted cancer
therapy, and the number of CDK4-related research articles and patents
has significantly increased in the last decade. Apart from these three US
FDA-approved selective CDK4/6 inhibitors, 15 CDK4/6 inhibitors are
in different phases of clinical trials as anticancer drugs as listed in Table 1
(Yuan et al., 2021).

5.2 S-phase targeted therapeutics

Cell cycle event at S-phase is governed by the DNA replication process; in
late G1 (after the restriction point), cyclin E binds to CDK2 for the phos-
phorylation of Rb leading to the activation of E2Fs transcription factor
(Grant & Cook, 2017). E2Fs accelerate the transcription of S-phase proteins
such as cyclin A and E. CDK2-cyclin A, CDK1-cyclin A, and CDK1-
cyclin B complex partner leads to the phosphorylation of Rb ensure the
cell cycle progression. CDK2-Cyclin A associated with S/G2 transition,
Table 1 Small molecule CDK inhibitors and proteins targets of drugs that impact cell cycle progression.
Clinical status/
Cell cycle Clinical trial
phases Drug targets Drugs Mechanism Application number References

Specific kinase inhibitor (Third Generation)

G1 CDK4/6 Abemaciclib Compete with ATP for the Advanced or metastatic US FDA Sledge et al.
(LY2835219) ATP-binding sites on breast cancer approved/ (2017) and
Verzenioa CDK4, and CDK6 NCT02441946 Hafner et al.
(2019)
CDK4/6 Palbociclib Inhibiting CDK4/6, thus For treatment of advanced, US FDA Santo, Siu, and
(PD-0332991) Ibrancea arrest cancer cell cycle also hormone receptor (HR) approved, Raje (2015)
targets the estrogen positive postmenopausal Launched 2015/
receptor positive breast breast cancer NCT04130152
cancer cells
CDK4/6 Ribociclib (LEE011) Selective CDK4/6 To treat adults with US FDA Hortobagyi
Kisqalia inhibitor, bind to the ATP hormone receptor approved, 2017/ et al. (2016)
cleft of CDK4 and CDK6 (HR)-positive, human NCT02586675
epidermal growth factor
receptor 2 (HER2)-
negative breast cancer
CDK4/6 Trilaciclib (G1T28) Potent and selective Chemotherapy induced US FDA Tan et al. (2019)
CDK4/cyclinD1 and myelosuppression in approved, 2021/
CDK6/Cyclin D3 Breast, NSCLC and small NCT02499770
inhibitor cell lung cancer
CDK4/6 Lerociclib (G1T38) Selective CDK4/cyclinD1 Used in combination with Phase I, II/ Bisi et al. (2017)
and CDK6/Cyclin D3 Osimertinib in NCT03455829
inhibitor EGFR-Mutant Non-Small
Cell lung cancer
Continued
Table 1 Small molecule CDK inhibitors and proteins targets of drugs that impact cell cycle progression.—cont’d
Clinical status/
Cell cycle Clinical trial
phases Drug targets Drugs Mechanism Application number References
S,G2 CDC7 PHA-767491 (NMS- Selective inhibitor of Used in advanced solid Withdrawn from Montagnoli
CDK9 11163541) CDC7 and CDK9, and off tumors Phase I clinical et al. (2008)
targets are CDK2/5/1 trial
GSK 3β,MK2,PLK-1,
CHK2
CDC7 XL-413 (BMS-863233) Selectively inhibiting Used in advanced solid Withdrawn from Koltun et al.
CDC-7 and other off tumors and hematologic Phase 1 and II (2012)
targets are PIM1, CK2 malignancies clinical trials
CDC7 LY-3143421 Selectively inhibiting Used for colorectal cancer, Phase Koltun et al.
CDC7 high grade serous ovarian I/NCT03096054 (2012)
cancer and non-small cell
lung cancer
CDC7 TAK-931 Selective and In various advanced solid Phase I/II/ Iwai et al.
(Simurosertib) ATP-competitive cell tumors NCT02699749 (2019)
division cycle 7 (CDC7)
kinase
CDK7 BS-181 Significantly reduced the Inhibits the cancer cell Not entered in Ali et al. (2009)
activity of CDK7 with growth of a range of tumor clinical studies
downregulation of cyclin types, including breast, yet
D1 and XIAP in GC cells lung, prostate and
colorectal cancer
CDK7 ICEC0942 (CT7001, Inhibits cell proliferation Metastatic, ER-positive Phase Patel et al.
Samraciclib) and induces cell cycle arrest Breast Cancer I/NCT04802759 (2018)
in G1 also regulating Pol II
dependent transcription
CDK7 is the CAK,
Phosphorylating the main
cell cycle CDK1/2/4/6
CDK7 THZ1 Covalent Investigated the therapeutic Not entered Kwiatkowski
cyclin-dependent kinase efficacy of THZ1 alone and clinical trial yet et al. (2014)
inhibitor in combination with
gemcitabine or cisplatin in
human UC (Urothelial
carcinoma) an in vitro and
in vivo
CDK7 YKL-5-124 Selective, Irreversible and Used to elicit immune Not entered in Olson et al.
Covalent CDK7 Inhibitor response signaling in small clinical studies (2019)
cell lung cancer (SCLC) yet
CDK7 SY-5609 Potent CDK7 inhibitor Used in an advanced solid Phase 1/ Sava, Fan,
that targets two tumor breast cancer, NCT04247126 Coombes,
fundamental processes in small-cell lung cancer, and Buluwela, and
cancer: transcription and cell pancreatic cancer Ali (2020)
cycle control
CDK7 SY-1365 Selective CDK7 inhibitor Advanced solid tumors Terminated after Sava et al.
ovarian cancer, and breast phase I clinical (2020)
cancer trial/
NCT03134638
Continued
Table 1 Small molecule CDK inhibitors and proteins targets of drugs that impact cell cycle progression.—cont’d
Clinical status/
Cell cycle Clinical trial
phases Drug targets Drugs Mechanism Application number References

Multiple kinase Inhibitors (Second-generation)

G1,S, CDK2 Dinaciclib ATP competitive and dual Acute Myeloid Leukemia Phase Ghia et al.
G2/M CDK5 (SCH727965) inhibitor of CyclinA/ I/NCT03484520 (2017) and
CDK1 CDK2, cyclin H/CDK7, Parry et al.
CDK9 Cyclin D1/CDK4, cyclin (2010)
E/CDK2, Cyclin B/CDK1
and TRKA, respectively
CDK2 Milciclib (PHA848125) ATP competitive and dual Advanced hepatic Phase II/ Otto and
inhibitor of CyclinA/ malignancies, Thymic NCT03109886 Sicinski (2017)
CDK2, cyclin H/CDK7, cancers and hepatocellular
Cyclin D1/CDK4, cyclin carcinoma
E/CDK2, Cyclin
B/CDK1 and TRKA,
respectively
CDK9 AT7519 Selective inhibitor of certain Advanced malignant solid Phase Otto and
CDK5 Cyclin Dependent Kinases neoplasm metastatic I/NCT02503709 Sicinski (2017)
CDK2 (CDKs) leading to tumor malignant solid neoplasm
regression and unresectable solid
neoplasm
CDK9 RGB-286638 In vitro cell-free kinase Inhibits proliferation of Withdrawn Otto and
CDK1 assays indicated that multiple myeloma cancer phase I clinical Sicinski (2017)
CDK2 RGB-286638 inhibits cell lines trial/
CDK4 CDK1, 2, 3, 4, 5, and 9 and NCT01168882
CDK3 is less active against CDK6
CDK5 and 7
 CDK2 SB1317 (TG02) Selective inhibitor of Hepatocellular carcinoma Withdrawn from Otto and
CDK2 and other off target clinical trial/ Sicinski (2017)
of JAK2 and FLT3 NCT03738111
G1, S CDK2/4/6 PF-06873600 Potent inhibitor of Advanced or metastatic Phase I/II/ Freeman-Cook
phase (Ebvaciclib) ATP-dependent serine/ breast cancer NCT03519178 et al. (2021)
threonine kinases
CDK2/4/6
CDK2/9, CYC-065 (Fadraciclib) Potent inhibition of Serous uterine carcinoma, Phase Frame et al.
CDK1/5/7 CDK9-mediated AML (acute my I/NCT05168904 (2020)
transcription, decreasing
levels of RNA polymerase
II C-terminal domain
serine 2 phosphorylation
Pan kinase inhibitors (First Generation)
G1/ CDK2/9, Roscovitine (Seliciclib, CDK inhibitor that In non-small cell lung Phase Ali et al. (2009)
S,S CDK1/5/7 CY-202) preferentially inhibits cancer and B-cell I/NCT00999401 and Jabbour-
multiple enzyme targets malignancies Leung et al.
including CDK2, CDK7 (2016)
and CDK9, which alter the
growth phase of treated
cells
G1/ CDK2, FN-1501 Inhibitor of various Monotherapy in advanced Phase Richardson
S,S CDK4/6, FLT3 tyrosine kinases such as solid tumors as well as in I/NCT03690154 et al. (2019)
CDK2/4/6, PDGFR, KIT refractory or relapsed
protein, anaplastic (AML)
lymphoma kinase (ALK)
and RET protein,
particularly potent
on FLT3
Continued
Table 1 Small molecule CDK inhibitors and proteins targets of drugs that impact cell cycle progression.—cont’d
Clinical status/
Cell cycle Clinical trial
phases Drug targets Drugs Mechanism Application number References

G1,S, CDK9, Alvocidib It is a potent AML, astrocytoma, breast Phase II/ Shapiro (2006)
G2/M CDK1/4/5/6/7, (Flavopiridol) Cyclin-Dependent Kinase cancer, CLL, endometrial NCT00445341
pankinase (CDK) inhibitor with cancer, gastric cancer,
preferential activity against GIST, glioma, HNSCC,
CDK9 kidney cancer, liver cancer,
lymphoma, melanoma,
NSCLC, pancreatic
cancer, small cell lung
cancer
S, G2/M CDK1/2/3/4 BAY-1000394 Inhibits the activity of Employed for small cell lung Phase Siemeister et al.
VEGFR (Roniciclib) cell-cycle CDKs CDK1, carcinoma and thyroid cancer I/NCT02457351 (2012)
CDK2, CDK3, CDK4,
and of transcriptional
CDKs CDK7 and CDK9
ATM/ATR targeted inhibitor
G1,S ATM/ATR Dactolisib (BEZ235) Dual ATP-competitive Treatment of patients with Phase II/ Mukherjee et al.
PI3K and mTOR inhibitor advanced solid tumors NCT01343498 (2012)
for p110α/γ/δ/β and
mTOR(p70S6K) also
Inhibiting ATR
Elimusertib Potent and highly selective Used in combination with Phase Wengner et al.
hydrochloride ATR (ataxia telangiectasia FOLFIRI (leucovorin I/NCT04535401 (2020)
(BAY-1895344 and Rad3-related) calcium, fluorouracil, and
inhibitor. irinotecan hydrochloride)
in treating patients with
stomach or intestinal
cancer
Checkpoint kinase targeted inhibitor
G1,S, CHK1 Prexasertib Small molecule checkpoint For the treatment of Phase Gatti-Mays
G2 (checkpoint (LY2606368) kinase inhibitor, mainly Leukemia, Neoplasm, I/NCT02514603 et al. (2020)
kinase-1)/ active against CHEK1, Breast cancer, and Ovarian
CHK2 with minor activity against cancer
(Checkpoint CHEK2
kinase-2)
MK-8776 Targeting cell cycle checkpoint Treatment of neoplasms, Phase Labroli et al.
(Scheme 900776) kinase 1 (Chk1) with hodgkin disease, adult I/NCT00779584 (2016)
potential radiosensitization erythroleukemia,
and chemosensitization lymphoma, non-hodgkin,
activities and myelogenous
leukemia, acute, among
others
UCN-01 Acts as an ATP Used in combination with Phase Zhao et al.
competitive inhibitor carboplatin in advanced I/NCT00036777 (2002)
targeting several kinases solid tumors
including protein kinase C
(PKC), Chk1, and Chk2
protein
WEE1 Inhibitor
S, WEE1 AZD1775 Highly selective, potent, Monotherapy in patients Phase Lallo et al.
G2/M checkpoint ATP competitive, small with locally advanced solid I/NCT02610075 (2018)
kinase molecule inhibitor of tumors, metastatic solid
Wee1 kinase tumors, and ovarian cancer
Continued
Table 1 Small molecule CDK inhibitors and proteins targets of drugs that impact cell cycle progression.—cont’d
Clinical status/
Cell cycle Clinical trial
phases Drug targets Drugs Mechanism Application number References

AUROR A and B kinase inhibitor

G2/M Aurora A and B Barasertib (AZD1152) Reversible, selective, Acute Myeloid Leukemia Phase Dennis et al.
kinases ATP-competitive I/NCT03217838 (2012)
inhibitor of Aurora B
kinase
Danusertib Small molecule ATP Patients with metastatic Phase II/ Fei et al. (2012)
(PHA-739358) competitive pan-aurora hormone refractory NCT00766324
(Aurora A/B/C) kinase prostate cancer
inhibitor that inhibits the
catalytic domain of aurora
kinases
PLK 1 Inhibitor
S, G2/M PLK1 (polo-like Volasertib Novel small-molecule Acute Myeloid Leukemia Phase Van den
kinase-1) targeted therapy that I/NCT01662505 Bossche et al.
blocks cell division by (2016)
competitively binding to
the ATP-binding pocket of
the PLK1 protein
BI 2536 Prevents PLK1’s Carcinoma, non-small-cell Phase McInnes and
enrichment at lung I/NCT02211833 Wyatt (2011)
kinetochores and
centrosomes, and when
added to metaphase cells, it
induces detachment of
microtubules from
kinetochores and leads to
spindle collapse.
Cell cycle targeted anti-cancer therapy 367

whereas CDK1-cyclin A and CDK1-cyclin B set up the initiation of mitosis

and it is involved in microtubule dynamics and chromosome condensation
for cell division resulting in the progression through the M-phase (Bertoli
et al., 2013). Therefore, CDK2 is a core cell cycle regulator in proliferating
cells that stays active from the late G1-phase to the S-phase. Deregulation of
CDK2 due to its overexpression of binding partners cyclin E1, cyclin E2,
and cyclin A, or loss of its endogenous inhibitors (the Cip/Kip family), or
its inappropriate expression may cause different types of cancer such as sarcoma,
melanoma, osteosarcoma, and breast, lung, ovarian, pancreatic, and thyroid
carcinomas. Cyclin B overexpression often results in increased CDK1 activa-
tion, which is again indulged with various types of tumors such as breast, colon,
prostate, thyroid, and NSCLC carcinoma. Dysfunctional CDKs have been
reported to cause abnormal cell proliferation, and chromosomal instability
resulting in human cancer and contributing to tumorigenesis and aggressive-
ness with poor overall survival for patients (Bai, Li, & Zhang, 2017).
Milciclib (PHA-848125) is a potent inhibitor of CDK2/Cyclin A and
tropomyosin receptor kinase A (TRKA). It is a small molecule that belongs
to the pyrazole (4,3-h) quinazoline family, with an effective antineoplastic
activity (Brasca et al., 2009; Caporali et al., 2010; Degrassi et al., 2010).
Milciclib also inhibits other CDKs, such as CDK1, CDK4, and CDK5, that
play crucial roles in the progression of the cell cycle from the G1 to the S
phase. Moreover, it shows effectiveness against different kinases, such as
SRC tyrosine kinase and splicing kinase families. Inhibition of these kinases
results in cell cycle arrest and apoptosis of tumor cells (Caporali et al., 2010).
Due to these unique characteristics of this molecule, Milciclib is considered
more advantageous keeps over other CDKs inhibitors. Recently, in 2020
Tiziana Life Science filed a patent on the use of Milciclib (Phase II clinical
trial) in combination with tyrosine kinase inhibitors for the treatment of
hepatocellular carcinoma, and other cancers such as NSCLC, pancreatic
and colon cancer, thymic carcinoma and thymoma (Tiziana Company, 2021).
Ebvaciclib (PF-06873600) is an inhibitor of CDK2, and CDK4/6
blocking the phosphorylation of pRb and limiting the proliferation of
OVCAR-3 ovarian cancer cells with EC50s of 19 and 45 nM, respectively
(Freeman-Cook et al., 2021). Inhibition of CDKs by PF-06873600 leads to
cell cycle arrest, induction of apoptosis, and inhibition of tumor cell prolif-
eration. It is now under phase-IA clinical trial for patients with advanced
breast cancer (Weiss et al., 2012).
Fadraciclib (CYC-065), CDK2 inhibitor, in combination with eribulin
a (Nontaxane microtubule inhibitor) approved for metastatic breast cancer
in triple-negative breast cancer (TNBC) (Frame et al., 2020). Recent inves-
tigation shows that myeloid cell leukemia 1 (MCL-1), an anti-apoptotic
368 Debarun Patra et al.

protein of the BCL-2 family, was downregulated after 6–8 h treatment of

Fadraciclib resulting in rapid induction of apoptosis in AML cell lines
(Chantkran et al., 2021). Prolonged treatment increases the efficacy of
CYC065. It is not only a pan CDK2/5/9 inhibitor but also a PI3K inhibitor,
thus exhibiting synergistic cytotoxicity in serous uterine carcinoma.
SU9516 is a small molecule selective CDK2 inhibitor chemically derived
from 3-substituted indolinone. It was identified via high-throughput
screening and examined to determine its effects on colon cancer cell kinase
activity, cell proliferation, cell cycle progression, and apoptosis (Lane et al.,
2001). SU9516 selectively inhibits CDK2 kinase activity, decreases ligand-
dependent and -independent cell cycle progression, and increases apoptosis.
The crystal structure of SU9516 in complex with CDK2 shows that inhibi-
tion of CDK2/Cyclin E and CDK1/Cyclin B1 in an ATP-competitive
manner, although at a two- to eightfold reduced potency. On the other
hand, it also exhibited non-competitive inhibition concerning ATP toward
CDK4/cyclin D1, with a 45-fold reduced potency. The X-ray crystal
structure revealed that SU9516-CDK2 interaction occurs at Leu83 and
Glu81 of the kinase. Reportedly, pRb acts as a negative regulator of cell cycle
transition and suppresses the expression of DHFR (Dihydrofolate reductase).
Application of SU9516 notably suppresses DHFR and improves sensitivity
toward MTX (Methotrexate) in human leukemic cells (Gao, Kramer,
Rahmani, Dent, & Grant, 2006; Lane et al., 2001; Yu, Lane, & Wadler, 2002).
Seliciclib (CY-202/R-roscovitine) is a purine analog of CDK inhibitor
that effectively inhibits CDK1, CDK2, CDK5, CDK7, and CDK9, with
little effect on CDK4/6, however, it showed high efficacy in the combina-
tion therapy (Cicenas et al., 2015; Raje et al., 2005). There are many CDK2
inhibitors in the preclinical development pipeline with a structurally large
number of scaffolds, notably, pyrido [2,3-d] pyrimidines, pyrrolo [2,3-d]
pyrimidines, aryl pyrimidines, and miscellaneous compounds. Most of these
compounds are classical CDK2 inhibitors that bind to the ATP binding site
and thus these, may suffer from specificity problems (Mahapatra, Prasad, &
Sharma, 2021). Therefore, developing a selective therapeutic CDK2
inhibitor may open a new door for treating various cancers.

5.3 G2 and M phase inhibitors

Mitotic CDK (CDK1 or CDC28) is an essential regulator of G2/M phase cell
cycle checkpoints that play irreplaceable roles in cell cycle regulation (Goranov
& Amon, 2010; Malumbres, 2011). CDK1/cyclin A complex oscillates during
each cell cycle and plays a vital role in the G2/M phase transition. Reportedly,
CDK1 overexpression has been noted in several cancers like epithelial
Cell cycle targeted anti-cancer therapy 369

ovarian cancer (EOC) and thus CDK1 inhibition is a potential therapy for
MYC-dependent breast cancer. Abrogation of the G2 checkpoint is a tacit
approach for the development of cancer cell-specific medicines.
Russell and Powell’s group reported that caffeine disrupts the G2 check-
point to sensitize G1 defective cancer cells (Powell et al., 1995; Russell et al.,
1995). Flavopiridol (VFP; alvocidib), is flavone derivative and US
FDA-approved drug. More than 50 clinical trials include VFP in the
United States, but clinical trial data showed a severe adverse effect in almost
half of the patients. AT-7519 is a small molecular inhibitor of CDK1,
CDK2, CDK4/6 and CDK9 and possesses strong anti-proliferative activity
against a wide range of human cancer cell lines and tumor xenografts,
including both solid tumors and hematological malignancies (Chen et al.,
2014; Zhang et al., 2021). AT-7519 induces apoptosis in multiple myeloma
cells and other B-cell malignancies by inhibiting RNA II polymerase (Santo
et al., 2010). The combination of AT-7519 and Cisplatin augments the
inhibitory effects in ovarian cancer cells in a dose-dependent manner.
AT-7519 (i) inhibits cell proliferation via decreasing activities of CDK1
and 2, and via inhibiting RNA transcription; (ii) inhibits migration via
suppressing epithelial–mesenchymal transition (EMT); and (iii) induces
apoptosis via decreasing MCL-1 and increasing pro-apoptotic protein
Bim in ovarian cancer cells (Squires et al., 2010). Voruciclib (also known
as P1446A-05 or P1446A) is flavone-based non-selective inhibitor of
CDK1, CDK9, and CDK4/6; currently in clinical trials in combination
with BRAF inhibitor (PLX4032) to treat advanced BRAF-mutant mela-
noma (Dey et al., 2017; Eliades et al., 2016). Mechanistic studies revealed
that P1446A-05 inhibits phosphorylation targets of CDK members, and
induces cell cycle arrest and apoptosis. Voruciclib has significant inhibitory
activity against cutaneous and uveal melanoma (Eliades et al., 2016).
Roniciclib (BAY-1000394) is an orally bioavailable pan-CDK inhibitor
effectively suppressing the activity of CDK1, CDK2, CDK3, CDK4,
CDK7, CDK9 and has been developed for the treatment of small cell lung
carcinoma, and other solid tumors (Ayaz et al., 2016; L€ ucking et al., 2013;
Siemeister et al., 2012). In the cell-based assay, it potentiates phosphory-
lation inhibition of CDK substrates, pRb, nucleophosmin, and RNA
polymerase II. BAY-1000394 showed more than additive efficacy when
combined with cisplatin and etoposide (Siemeister et al., 2012) (see Table 1).

5.4 Inhibitors of WEE1 and CHK1 kinases

Cell cycle transition could be halted at the critical G2/M checkpoint by an
oncogenic nuclear tyrosine kinase WEE1 that inhibits cyclin B-CDK1
370 Debarun Patra et al.

complexes through inhibitory phosphorylation at Tyr15 in CDK1. During

the G2/M transition, cells in the absence of DNA damage, polo-like kinase 1
(PLK1) phosphorylates WEE1 leading to its degradation via ubiquitin
ligase complex (Lindqvist, Rodrı́guez-Bravo, & Medema, 2009). PLK1 also
phosphorylates Cdc25 phosphatase which, in turn, activates CDK1 via
dephosphorylation (Boutros, Lobjois, & Ducommun, 2007). Thus, acti-
vated CDK1 upon binding with cyclin B promotes cell entry into mitosis
(O’Farrell, 2001). Normal cells repair damaged DNA during G1 arrest;
however, the majority of cancer cells lack G1–S checkpoint regulation
and therefore relied on the function G2/M checkpoint for repairing dam-
aged DNA. Therefore, WEE1 kinase is a crucial component that allows
DNA repair before entry into the mitotic phase. WEE1 is overexpressed
and activated in several cancers, notably in leukemias (Ghelli Luserna Di
Rorà et al., 2018; Mancini et al., 2022), thereby circumventing apoptosis
via mitotic catastrophe. The pyridopyrimidine, PD0166285, was the first
identified small-molecule WEE1 inhibitor that impairs the G2/M check-
point in cancer cells (Wu, Nielsen, & Clausen, 2015). Although
PD0166285 is a potent WEE1 inhibitor in various cancer cells, however,
due to its non-selective nature it can also target various other tyrosine
kinases such as MYT1, c-Src, EGFR, FGFR1, and PDGFR-b (Panek
et al., 1997) thus limiting its use as targeted therapy. Screening of a small
chemical compound library revealed the discovery of the potent WEE1 inhib-
itor AZD1775 (also known as MK1775) (Hirai et al., 2009). It is a potent
inhibitor of WEE1 (IC50 ¼ 5 nM) and exhibits more than 100-fold selectiv-
ity over other kinases. A carboxylate methyl-ester derivative of AZD1775,
CJM061 inhibits WEE1 similar to AZD1775 but exhibits a synergistic
effect when combined with cisplatin in medulloblastoma cells (Matheson
et al., 2016). There are several clinical studies are ongoing for AZD1775
(MK1775), against a variety of cancer types. In the majority of these studies,
AZD1775 is used in combination with different DNA-damaging agents
such as carboplatin, cisplatin, docetaxel, and others, with only a few studies,
including it as monotherapy.
The cell cycle checkpoint regulator protein kinases, mutated ATM
protein kinase or ATR protein kinase and the major downstream effector
protein CHK1, prevent G2/M entry of the cells with damaged or incom-
pletely replicated DNA when the cells are challenged by DNA-damaging
agents or chemotherapeutic drugs for cancer treatment. DNA damage
stimulates DNA damage response (DDR) via ATM or ATR protein kinase
pathways which preferentially depend on the type of genotoxic stress
(Do, Doroshow, & Kummar, 2013). ATM is recruited and activated in
Cell cycle targeted anti-cancer therapy 371

response to ionizing radiation, and agents that cause double-strand DNA

breaks. Activated ATM phosphorylates and activates CHK2, which phos-
phorylates Cdc25C at serine 216 leading to its recognition by 14–3-3σ
promoting nuclear export and cytoplasmic sequestration thus inactivating
phosphatase activity of Cdc25C (Matsuoka et al., 2000). Inhibition of
Cdc25C phosphatase activity, in turn, results in the persistence of inhibitory
phosphorylation of the CDK1/cyclin B complex and maintaining CDK1 in
an inactive form and preventing entry into mitosis (Boutros et al., 2007).
Conversely, ATR is recruited and activated by the genotoxic stresses that
cause single-strand DNA breaks ( Jazayeri et al., 2006). Activated ATR
phosphorylates and activates CHK1 that phosphorylates both WEE1 and
Cdc25C causing activation of WEE1 kinase activity and inhibition of
Cdc25C phosphatase activity. While activated WEE1 mediates inhibitory
phosphorylation of CDK1 at Tyr15 residue, the inactivated Cdc25C pre-
vents the removal of inhibitory phosphorylation from CDK1. These results
in the inactivation of CDK1–cyclin B complex promoting cell-cycle arrest
in G2 and allowing enough time for DNA repair.
Initial studies on the development of CHK inhibitors, UCN-01
(7-hydroxystaurosporine), XL844, and CBP501 were identified as potent
inhibitors of CHK1/2, however, the clinical application of these inhibitors
was limited due to their nonspecificity. As a potent CHK inhibitor, AZD7762
mainly suppresses CHK1-mediated phosphorylation of Cdc25C (Zabludoff
et al., 2008). Although AZD7762 serves as a dual inhibitor of CHK1
and CHK2, however, its function mainly depends on the suppression of
CHK1. The clinical trial of AZD7762 was terminated due to the multiple
adverse effects including cardiac toxicity (Sausville et al., 2014). LY2603618
is the first selective and potent CHK1 inhibitor, wherein piperidine moiety
was replaced with morpholine, exhibiting selective inhibition of CHK1
without the risk of cardiac toxicity (King et al., 2014). However, the clinical
studies of LY2603818 alone or in combination with gemcitabine or
pemetrexed and cisplatin did not produce promising effects against different
cancers. The other CHK1-specific inhibitor MK-8776 (Scheme 900776)
has also been investigated in complex tumors as a monotherapy, or in com-
bination with gemcitabine, and cytarabine in patients with relapsed acute
leukemia (Daud et al., 2015; Karp et al., 2012). LY2606368 (Prexasertib)
is a dual CHK1/2 inhibitor (King et al., 2015) for which several clinical trials
have been initiated. Preclinical research has been conducted on the orally
accessible CHK1 antagonists CCT244747 and CCT245737 in many cancer
types (Neizer-Ashun & Bhattacharya, 2021). With the goal of increasing
the proportion of apoptotic death of cells and reducing cell escape
372 Debarun Patra et al.

mechanisms and ultimately drug resistance, various combinations of

Danusertib or volasertib with a WEE1 inhibitor (AZD1775) have been
studied (Mancini et al., 2022). Treatment with CHK1/WEE1 dual inhib-
itors, PD-321852 or PD-407824 effectively sensitized pancreatic cancer
cells to gemcitabine (Parsels et al., 2009). Moreover, recently developed
CHK1 inhibitors, S1181 and the CHK1/2 dual inhibitor V158411, signif-
icantly potentiated p53-defective cancer cells against the various chemother-
apeutic agents (Koh et al., 2015; Massey et al., 2015) (see Table 1).

5.5 Aurora kinase and polo kinase inhibitors

Aurora kinase (AURK) belongs to the family of serine/threonine kinases
that contains three members: Aurora A (AURKA), Aurora B (AURKB),
and Aurora C (AURKC), wherein both AURKA and AURKB play a
critical role in the regulation of cell division during mitosis. During the
late G2 phase, AURKA expression rises and spikes at prometaphase.
The expression of AURKB, in contrast, surges around metaphase until
the termination of mitosis. Ajuba, Bora, and TPX2 must engage with
AURKA for it to be activated, which causes its autophosphorylation.
Similar to this, following interaction with CPC members, AURKB is trig-
gered by autophosphorylation of the T-loop (Thr232) (Li et al., 2015).
AURKA and AURKB function as oncogenes promoting tumorigenesis in
multiple types of cancer including solid tumors and hematological malignan-
cies. Although several inhibitors of AURKA have been developed, however,
only a few have shown efficacy in clinical trials such as MLN8237, ENMD-
2076, and MK-5108 (Du, Huang, Liu, Li, & Dong, 2021). Successive gen-
erations of blockers can deliberately target AURKA or AURKB, but previous
models of Aurora kinase inhibitors inhibit both AURKA and AURKB with-
out discrimination (Bavetsias & Linardopoulos, 2015; Green, Woolery, &
Mahadevan, 2011; Li et al., 2015). Polo-like kinase 1 (PLK1) plays a crucial
role in several cellular functions, including, but not limited to, the regulation
of mitosis, DNA replication, and epithelial–mesenchymal transition. It has
been observed that PLK1 overexpression and activation are critically associ-
ated with uncontrolled cell proliferation and poor prognosis in cancer
patients. Thus, PLK1 considered a promising antitumor target for developing
anticancer therapeutics. As antitumoral medications, numerous PLK1 kinase
antagonists have been established. Clinical trials are being conducted on the
following drugs: BI 2536, volasertib, NMS-P937, GSK4661364A, HMN-
214, and TAK-960 (Yim, 2013). Fig. 2 explains the major drugs that control
the cell cycle and its regulators.
Fig. 2 See figure legend on next page.
374 Debarun Patra et al.

6. Cancer cell proliferation inhibitors

To manage cellular connections, multicellular organisms have coordi-
nated systems of cell signaling. These intricate signaling networks regulate
healthy embryonic development and are in charge of the body’s immune
and inflammatory reactions to injury and infection. The identification of
several factors that influence the growth of almost all cell types has been
made possible by the discovery of nerve growth factor (NGF) and epidermal
growth factor (EGF), respectively. Growth factors, cytokines, and hormones
that engage with particular membrane receptors can start a chain reaction of
intracellular biochemical signals that activate and repress different groups of
genes. Developmental defects and many chronic diseases, including cancer,
are intricately related to genetic anomalies in growth factor signaling
pathways. A series of genetic events, including excessive production of dif-
ferent growth factors or uncontrolled regulation of their receptor activation
or the downstream signaling molecules activation, leads to the development
of malignant cells. Increased cell division by external or internal stimulation

Fig. 2 Major cell cycle regulatory proteins inhibitors (CDK inhibitors) under clinical eval-
uation. Cyclin-dependent kinases (CDKs) and the regulatory components of these
enzymes, called cyclins, regulate the cell cycle by temporally controlling kinase activity
and substrate selectivity. (A) CDK-cyclin complexes, comprising 10 cyclins from 4 differ-
ent classes, a mitotic CDK (CDK1), and major 3 interphase CDKs (CDK2, CDK4, and CDK6),
are involved in the course of the cell cycle (the A-, B-, D-, and E-type cyclins). Other
transcriptional CDKs regulators are CDK8, CDK9, CDK12 and CDK13 and their cyclin
partners are Cyclin C, Cyclin T, and Cyclin k, respectively. Two different families of
cyclin-dependent kinase inhibitors (CKIs) work to inhibit the activity of CDKs: the inhib-
itor of kinase (INK) family, which consists of four structurally related proteins (p16INK4A,
p15INK4B, p18INK4C, and p19INK4D), and the CDK-interacting protein/kinase inhibitory pro-
tein (CIP/KIP) family, which (p21Cip1, p27Kip1, and p57Kip2). The CIP/KIP proteins can bind
all of the CDKs that control the cell cycle, in contrast to members of the INK family
that only inactivate CDK4 and CDK6. Over the past 20 years, several small-molecule
kinase inhibitors have been created because dysregulated CDK activity is prevalent
in a wide range of malignancies and illnesses linked to senescence. Currently, there
are two classes of these inhibitors: those that target the family more broadly, such as
first-generation (flavopiridol and roscovitine) and second-generation (dinaciclib and
AT7519) inhibitors of multiple CDKs, and those that are CDK4/6 selective, also known
as the third generation of inhibitors, including palbociclib, ribociclib, and abemaciclib.
(B) Other CDKs (CDK8, 9, 12, 13) were found to be dysregulated and potentiate cancer.
Clinically approved and under clinical trial, drugs target these CDKs. New proteins that
affect cell division are frequently discovered, despite the fact that the cell cycle is a
highly complex process that has been extensively documented in the literature.
Cell cycle targeted anti-cancer therapy 375

is undoubtedly a common factor in the development of many human malig-

nancies, according to epidemiological studies. The term “increased” can
refer to an increase in the rate of mitosis above the baseline rate or to the
division of a subpopulation of cells that wouldn’t normally divide. Given
a constant rate of DNA damage, the degree of irreparable DNA damage
depends on the rate of cell division because a DNA error cannot be corrected
if the cell undergoes unregulated division.
Growth factors (GF) have a major role in the proliferation of cancer cells.
Previous literature highlighted a reduced need for serum for the growth
of neoplastically transformed cells and that can be met by (a) activating
autologous GF synthesis (“autocrine” activation), (b) creating an altered
GF receptor, or (c) activating a post-receptor pathway that avoids the need
for GF receptors activation (Slattery et al., 2013). Certain proto-oncogenes
(such as myc and fos), whose products may influence the transcription of
other genes required for the stimulation of cell proliferation, have been dem-
onstrated to increase transcription in response to growth stimuli (Dang,
1999; Stine, Walton, Altman, Hsieh, & Dang, 2015).
Epidermal Growth Factor: Cohen’s initial description of EGF as a peptide
that would promote early tooth emergence and eyelid opening in newborn
mice led to its purification and the discovery of its capacity to promote the
growth of cultured cells. There are currently no known tumors that produce
EGF, but they may ectopically reactivate embryonic genes that produce an
EGF-like molecule. EGF ligands signal through a group of receptor tyrosine
kinases called epidermal growth factor receptors (EGFRs, also called the
ERBB receptors). The receptor tyrosine kinases in the ERBB family, which
also comprises ERBB1, ERBB2, ERBB3, and ERBB4, have comparable
structural characteristics. The Ras-Raf-MAP-kinase pathway, which has
been most widely studied, appears to represent a significant ERBB family
of signaling pathways (Wang, 2017; Wieduwilt & Moasser, 2008). The
overproduction of ligands or the constitutive activation of receptors is only
a few examples of the mechanisms that have been identified as contributing
to the dysregulation of the EGF pathway in cancer. There have been numer-
ous reports of ERBB1 mutations in the ATP-binding cleft of the kinase
domain in lung cancer. Such mutations improve ERBB1’s capacity to form
heterodimers with other members of the ERBB family and have the poten-
tial to activate downstream signaling pathways (Wee & Wang, 2017).
Furthermore, EGFR exons 2 to 7 that are deleted to create the oncogenic
EGFRvIII mutant are frequently found in glioblastomas (An, Aksoy, Zheng,
Fan, & Weiss, 2018). Additionally, ERBB1 genomic amplification has been
376 Debarun Patra et al.

found in malignancies of the ovary, pancreatic, breast, head and neck. Breast
cancer typically exhibits ERBB2 amplification and overexpression, which is
associated with a poor prognosis and resistance to taxane chemotherapy.
Through delayed ligand-induced degradation, overexpression activates
the EGFR-dependent pathway (Liu & Ashour Ahmed, 2016; Sigismund,
Avanzato, & Lanzetti, 2018). EGFRs (ERBB) have been a special focus
for targeted therapy against breast cancer ( Johnston et al., 2006).
Herceptin® (Trastuzumab) and Erbitux® (Cetuximab) are monoclonal anti-
bodies developed to target EGFR and EGF, respectively, for breast cancer.
Tykerb® (Lapatinib) falls under the category of Tyrosine kinase inhibitor
(TKI) against ERBB1 and ERBB2 (Moy, Kirkpatrick, Kar, & Goss, 2007).
Transforming growth factor beta (TGFβ): Many physiological processes,
including cell adhesion, migration, differentiation, apoptosis, and the
choice of cell fate, are influenced by the transforming growth factor beta
(TGF) pathway (Baba et al., 2022; Kubiczkova, Sedlarikova, Hajek, &
Sevcikova, 2012). It is crucial for germline determination and patterning
during embryogenesis (Gordeeva, 2019). Three TGF isoforms, 4 activin
chains, the protein nodal, 10 bone morphogenic proteins (BMPs), and
11 growth and differentiation factors make up the transforming growth
factor family of ligands (GDFs) (Morikawa, Derynck, & Miyazono, 2016).
TGFBR2 is frequently mutated in human cancer, and these conserved muta-
tions frequently result in pathway inactivation. Both microsatellite instable
(+MIN) and microsatellite stable (MIN) alterations in cancer frequently
target the TGFBR2 gene (Biswas et al., 2008; Shima et al., 2011).
Furthermore, a microsatellite repeat region in the TGFBR2 gene has been
linked to both inherited and spontaneous colon cancers (Liu & Ashour
Ahmed, 2016). The SMADs are the sole downstream targets that are known
to be unique to the TGF-β family. Regions of the human locus 18q21
that encode SMADs 2 and 4 are frequently altered or deleted entirely in cases
of colon and pancreatic cancer. Approximately, 90% of pancreas cancer
cases show a deletion at 18q21, in the regions that harbor DPC4 (Deleted
in Pancreatic Carcinoma; SMAD4) and DCC (Deleted in Colorectal
Carcinoma) genes. Further research narrowed the deletion in pancreatic
cancer to 18q21.1, which includes DPC4, and disqualifies DCC as the
mutation target (Rane, Lee, & Lin, 2006). Through its cytostatic and
apoptotic effects, TGF causes a long-lasting anti-proliferative effect in the
early stages of tumor development. The overexpression of p21 and p15
and the subsequent suppression of CDK-mediated phosphorylation of
retinoblastoma protein, which stops the cell cycle, is regarded to be the
Cell cycle targeted anti-cancer therapy 377

key components of the cytostatic mechanism. TGF also inhibits c-Myc tran-
scription through a SMAD3-dependent mechanism. The TGF-induced
early response gene (TIEG1), the death-associated protein kinase (DAPK),
and the SH2-domain-containing inositol-5-phosphatase (SHIP) are examples
of SMAD transcriptional complexes that are involved in the regulation of
some pro-apoptotic target genes (Su, Yang, Xu, Chen, & Yu, 2015). It is
believed that the loss of this tumor-suppressing ability of TGF is a crucial
stage in the development of cancer. TGF signaling, however, is assumed
to be overexpressed in established tumors to produce a local immunosup-
pressive environment that promotes tumor development and worsens the
pro-invasive and metastatic characteristics of tumor cells. The down-
regulation of TIMP-1, which triggers the development of a number of
matrix metalloproteinases (MMPs) that cause the extracellular matrix to
break down and facilitate invasion, has been linked to the loss of SMAD3
expression in choriocarcinoma cells. Through its direct impact on VEGF
expression and its indirect action on the production of angiogenic cytokines
by monocytes, TGF also functions as a potent inducer of angiogenesis.
TGF signaling is important in bone metastasis, according to in vivo models
of breast cancer metastasis (Liu & Ashour Ahmed, 2016). Additionally,
several signaling pathways, including SMADs, PI3K/Akt, RHOA, and p38
MAPK, have been linked to TGF-induced epithelial-mesenchymal transition
(EMT) (Siegel & Massagu
e, 2003). Antisense oligonucleotides targeting
TGFβ2 mRNA constitute the drug Trabedersen® (Schlingensiepen
et al., 2011).
Hepatocyte growth factor (HGF): Hepatocyte growth factor (HGF) was
first discovered as a growth factor present in rat platelet that enhanced
DNA synthesis in primary cultured rat hepatocytes (Nakamura, Teramoto,
& Ichihara, 1986). The MET receptor tyrosine kinase, a receptor of HGF,
was linked to several physiological and pathological processes. Through a
variety of processes, such as transcriptional dysregulation, insufficient degra-
dation, receptor crosstalk, or synergy in downstream signaling cascades,
the normal control of HGF and MET is lost in malignancies. Mice with
induced germ-line mutations of the HGF pathway molecules develop a range
of cancers, including carcinomas, lymphomas, and sarcomas (Moosavi,
Giovannetti, Saso, & Firuzi, 2019). Basal-like carcinomas develop when
MET is conditionally activated in the mammary gland, and MET over-
expression is seen in many tumor types, including lung and renal carcinomas.
The stimulation of this system causes the PI3K/AKT and RAS/MAPK
pathways to remain activated for a prolonged time, increasing cell growth,
378 Debarun Patra et al.

proliferation, and resistance to apoptosis. Endothelial cell proliferation and

angiogenesis are both effectively induced by HGF/MET signaling.
Increased VEGFA synthesis and decreased thrombospondin production
are caused by MET activation, which improves angiogenesis. Through its
function in controlling cytoskeleton, regulated by RAS/MAPK and
RAC1/CDC42, MET also plays a significant role in encouraging the spread
of cancer cells (Bottaro et al., 1991). METMab® is a monoclonal antibody
developed against MET, reducing tumor burden ( Jin et al., 2008).
Platelet-derived growth factors: Both autocrine and paracrine PDGF signal-
ing have been implicated in modifying tumor behavior. Glioblastoma, soft
tissue sarcomas, and breast cancer have all been linked to autocrine PDGF
signaling, which promotes growth, survival, invasion, and metastasis.
PDGF isoforms, PDGFA, PDGFC, and PDFGR- are highly expressed in
a variety of tumors (Zou et al., 2022). In some gliomas, elevated expression
of PDGF is often associated as a result of activation by other growth factors
such as TGF-b. Additionally, glioblastoma and esophageal squamous cell
carcinoma have been linked to gene amplification. Activating mutations
and chromosomal rearrangements also result in autocrine PDGF signaling
in addition to its enhanced expression. For instance, PDGFR gain of func-
tion mutations is common in gastrointestinal stromal tumors, even when
KIT mutations are absent. Several myeloid diseases, including leukemia,
include PDGF receptor translocations, such as the ETV6-PDGFRB fusion,
which causes constitutive activation of the receptor (Medeiros et al., 2004).
Gleevec® (Imatinib) is a Tyrosine kinase inhibitor (TKI) effective against
both PDGFR-α and PDGFR-β originally used for the management of
malignancies (Druker, 2002).

6.1 Hormone, hormone receptors, and cancer cell proliferation

Proto-oncogenes, growth factors, and other genes and proteins that cause
cells to enter the cell cycle are all under the control of estrogens. In addition,
cyclins, a protein directly involved in the regulation of the cell cycle, are
also under estrogen control (p53, BRCA1). The creation of the AP-1 tran-
scription activating complex, which is made up of DNA-binding Jun-Jun or
Jun-Fos dimers is facilitated by estrogens. Other growth-stimulating genes
controlled by estrogens include the proto-oncogenes c-myc and c-myb as
well as the oncogene ras. IBRANCE® (Palbociclib) targets CDK4/6 further
inhibit the Estrogen receptor (ER) (Ciocca & Fanelli, 1997). Faslodex® is a
fulvestrant whereas Aromasin® (Exemestane) inhibits the enzyme aromatase
to target Estrogen (Howell, 2006).
Cell cycle targeted anti-cancer therapy 379

The cell cycle machinery and the progesterone receptor (PR) collaborate to
promote tumor cell growth. The PR status has been favorably correlated
with the overexpression of cyclins (cyclin D) in breast cancers. Application
of progesterone inhibitors in breast cancer cell lines for an extended period
significantly inhibits the activity of cyclin D1/CDK4, cyclin D3/CDK4,
and cyclin E/CDK2 complex kinases as well as overall expression of cyclin
D1, cyclin D3, and cyclin E (Skildum, Faivre, & Lange, 2005). Inhibitors
of cancer cell proliferation factors in clinical development and exercise were
presented in Table 2.

Table 2 Inhibitors of cancer cell proliferation factors in clinical development and

exercise.
Clinical trial
Drug Target Type performed References
Herceptin® ERBB2 Monoclonal HER2 +ve Aaronson (1991),
(Trastuzumab) (EGFR) antibody breast cancer Johnston et al. (2006),
and stomach and M€ uller et al.
cancer (2018)
Erbitux® EGFR Monoclonal Metastatic Johnston et al. (2006),
(Cetuximab) antibody head and neck Preston-Martin, Pike,
cancer, Ross, Jones, and
colorectal Henderson (1990),
cancer and Vokes and Chu
(2006)
Tykerb® ERBB1 Tyrosine kinase HER2 +ve Browne, O’Brien,
(Lapatinib) and inhibitor (TKI) breast cancer Duffy, Crown, and
ERBB2 O’Donovan (2009),
Liu and Ashour
Ahmed (2016), and
Moy et al. (2007)
TGFβ2 Anti-sense Brain tumors Schlingensiepen et al.
Trabedersen® mRNA DNA as well as solid (2011), Sigismund
oligonucleotides tumors of et al. (2018), and
skin, colon Vallières (2009)
and pancreas
METMab® MET One-Armed Renal cell Jin et al. (2008),
(Onartuzumab) (HGF) humanized carcinoma Johnston et al. (2006),
antibody (RCC), and Moosavi,
(OA-AB) pancreatic Giovannetti, Peters,
cancer and and Firuzi (2021)
Medullary
thyroid cancer
(MTC)
Continued
380 Debarun Patra et al.

Table 2 Inhibitors of cancer cell proliferation factors in clinical development and

exercise.—cont’d
Clinical trial
Drug Target Type performed References
®
Gleevec PDGFR-α Tyrosine kinase Chronic Druker (2002),
(Imatinib) and inhibitor (TKI) myeloid Hernández-Boluda
PDGFR-β leukemia and Cervantes (2002),
(CML) and Moy et al. (2007)
IBRANCE® Estrogen Targeting HR +ve Ciocca and Fanelli
(Palbociclib) receptor CDK4/6 (Hormone (1997), Loibl et al.
(ER) receptor) and (2021), and Rane
HER2 –ve et al. (2006)
breast cancer
Faslodex® Blocks ER ER antagonist HR +ve Ciocca and Fanelli
(Fulvestrant) metastatic (1997), Howell et al.
breast cancer (2000), Siegel and
Massagu
e (2003)
Aromasin® Estrogen Aromatase ER +ve Paridaens et al. (2000),
(Exemestane) inhibitor breast cancer Schlingensiepen
(Anti-estrogen) et al. (2011)

7. Conclusion
Although cancer therapy was initiated more than a century ago,
however, the complications of this disease were rapidly elucidated in the
last 40–50 years. The discovery of fundamental cell cycle regulators was
initiated 35 years ago, but anti-cancer therapeutics against cell cycle regula-
tors maximized in the past one and half decades (Kim, Roh, Wee, & Kim,
2016). Our knowledge and understanding of these molecules involved in
cancer proliferation have significantly improved, and that helps to develop
potential therapy. Rapid investigation of the cell cycle also made it possible
to develop novel chemical compounds that selectively inhibit target mole-
cules. Interestingly, selective inhibitors like Palbociclib, Ribociclib target
CDK4/6 and block RB phosphorylation in cancer cells and received
FDA approval for the treatment of breast cancer patients (Hamilton &
Infante, 2016). These results encouraged further the development of
more potent and selective CDK4/6 inhibitors for monotherapy or combi-
natorial therapy. Antibody-drug conjugates against the checkpoint regula-
tors were recently developed targeting individual CDKs and that may
Cell cycle targeted anti-cancer therapy 381

accelerate anti-tumor efficacy with reduced adversity. Moreover, small

molecule inhibitors like Milciclib, targeting CDK2 showed profound
anti-neoplastic activity in liver cancer (Remon, Lindsay, Bluthgen, &
Besse, 2016). Recently developed CDK2 and CDK1 inhibitors hold prom-
ising potential for anti-cancer therapy against different types of malignancies.
Apart from targeting CDKs, several other kinases that are involved in cell
cycle regulations such as WEE1, CHK1/2, AURKA/B, and PLK1 are also
considered potential targets for cancer therapy. MK-8776 and AZD1775 are
selective inhibitors of CHK1 and WEE1, respectively (Sakurikar, Thompson,
Montano, & Eastman, 2016). MK-8776 potentiates apoptosis and cell death
in solid tumor as well as leukemia whereas AZD1775 is used in NSCLC and
pancreatic cancer. PLK1 inhibitors, Rigosertib showed antitumor efficacy in
patients having myelodysplastic syndromes (O’neil et al., 2015). Quite a few
drugs have been generated to target AURKA/B. Alisertib, a selective and
potent inhibitor of AURKA causes polyploidy and mitotic arrest, as well as
senescence or death in different types of cancer including B-cell and T-cell
non-Hodgkin lymphoma, breast, small-cell lung, non-small-cell lung cancer
(Otto & Sicinski, 2017).
As cell cycle progression is closely linked with the proliferation of cancer
cells, the growth factors and hormones extensively activate oncogenes
and survival signaling pathways to constitutively activate the cell cycle.
Trastuzumab, a monoclonal antibody targeting EGFR used in breast cancer.
Tyrosine kinase inhibitor (TKI), Imatinib targets both PDGFR-α and
PDGFR-β used in leukemia and a few other cancer subtypes (Ranieri
et al., 2013).
Recent advancement of knowledge in the field of cell cycle regulation
encourages the development of advanced, potent, and selective molecules
that could effectively manage different cancer cells by targeting cell cycle
regulators with the least side effect in near future. Along with small molecule
synthetic inhibitors, and monoclonal antibodies, selective therapy can
be executed by targeting cellular transcriptome level via anti-sense oligo
therapy pertinent to specific mRNA or miRNAs that critically regulate cell
cycle events. In a particular phase 1 clinical study with MRX34, a
miRNA-based therapy using a liposomal formulation of miR-34a mimic,
was used in patients with solid tumors. Although it did not receive resilient
success in patients, however, it sharply shed proof-of-concept for miRNA
therapy in cancer (Hong et al., 2020). Since tumor relapse often occurs with
anti-cancer drugs, therefore, it is highly required to perform extensive
exploration on the drug insensitivity mechanism in patients to generate
low-dose with high sensitivity and safer therapeutic options.
382 Debarun Patra et al.

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