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Task-1-CDK9-PROTAC-components

The document outlines components and example compounds for CDK9 PROTACs, detailing various warheads, anchors, and linker motifs. Specific compounds like Wogonin and AT7519 are highlighted with their IC50 values and SMILES strings for visualization. Additionally, hypothetical PROTAC candidates are presented, demonstrating potential combinations of these components.

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Ruhani Moushi
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41 views

Task-1-CDK9-PROTAC-components

The document outlines components and example compounds for CDK9 PROTACs, detailing various warheads, anchors, and linker motifs. Specific compounds like Wogonin and AT7519 are highlighted with their IC50 values and SMILES strings for visualization. Additionally, hypothetical PROTAC candidates are presented, demonstrating potential combinations of these components.

Uploaded by

Ruhani Moushi
Copyright
© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
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Download as PDF, TXT or read online on Scribd
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CDK9 PROTAC components and example compounds

Warheads and anchors are shown with proposed attachment sites (linker = R1).
IC50 = half-maximal inhibitory concentration
Hint: the SMILES strings can be used to visualise the formulae of the compounds in
a chemical drawing software such as Marvin (https://freetrial.marvin.cxn.io/).

1. CDK9 PROTAC components


1.1 CDK9 warheads

• Wogonin (CDK9 IC50 = 0.19 μM; CDK7 IC50 = 12.3 μM)

SMILES: COC1=C(C=C(C2=C1OC(=CC2=O)C3=CC=CC=C3)O)O

• AT7519 (CDK9 IC50 <10 nM; CDK7 IC50 =24 μM)

SMILES: C1CNCCC1NC(=O)C2=C(C=NN2)NC(=O)C3=C(C=CC=C3Cl)Cl

1.2 Common PROTAC anchors

• Pomalidomide (targeting CRBN)


Note: Shown below is a derivative of pomalidomide, in which the (-NH2) amino
group was substituted by an amide (-NH-CO-) often used to attach the linker

SMILES: CC(=O)NC1=CC=CC2=C1C(=O)N(C1CCC(=O)NC1=O)C2=O
• VH032 (targeting VHL)

SMILES:
CC(N=CS1)=C1C2=CC=C(CNC([C@@H]3C[C@@H](O)CN3C([C@H](C(C)(C)C)N
C(C)=O)=O)=O)C=C2

1.3 Common linker motifs

Note: You may want to combine these motifs to generate linkers of different
properties and lengths. The formulae on the right of the motifs show how to attach
them together.

• Alkyl

SMILES: C

• PEG

SMILES: COC

• 1,2,3-Triazole (typically generated in a click chemistry reaction, which will be


covered in Task 2)

SMILES: N1C=CN=N1
2. Example PROTAC compounds based on these linkers

• Compound 11c from Bian et al., 2018 (the initial compound)

Wogonin Triazole 7x Alkyl

Pomalidomide (amide
derivative)
SMILES:
OC1=CC(O)=C(OCC2=CN(CCCCCCCC(=O)NC3=CC=CC4=C3C(=O)N(C3CCC(=O
)NC3=O)C4=O)N=N2)C2=C1C(=O)C=C(O2)C1=CC=CC=C1

• Hypothetical PROTAC candidate 1

AT7519 Alkyl Triazole 2x PEG


(+ amide
bridge)

Pomalidomide (amide
derivative)
SMILES:
ClC1=CC=CC(Cl)=C1C(=O)NC1=C(NN=C1)C(=O)NC1CCN(CCN2C=C(CCOCCOC
(=O)NC3=CC=CC4=C3C(=O)N(C3CCC(=O)NC3=O)C4=O)N=N2)CC1
• Hypothetical PROTAC candidate 2

AT7519 2xAlkyl Triazole PEG VH032

SMILES:
CC1=C(SC=N1)C1=CC=C(CNC(=O)[C@@H]2C[C@@H](O)CN2C(=O)[C@@H](N
C(=O)COCCC2=CN(CCCN3CCC(CC3)NC(=O)C3=C(NC(=O)C4=C(Cl)C=CC=C4Cl)
C=NN3)N=N2)C(C)(C)C)C=C1

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