Structure-Based Design of Selective Noncovalent CDK12 Inhibitors
Jeffrey W Johannes1, Christopher R Denz1, Nancy Su2
1Oncology, IMED Biotech Unit, AstraZeneca, Boston, MA, USA.
Chemmedchem
|December 22, 2017
Summary
Researchers developed selective small molecule inhibitors of Cyclin-dependent kinase (CDK) 12. These compounds decrease DNA-damage-response gene transcription and show toxicity to cancer cells, offering potential for new cancer therapies.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Oncology
Background:
- Cyclin-dependent kinase (CDK) 12 regulates DNA-damage-response genes.
- CDK12 inhibition sensitizes BRCA wild-type cells to PARP inhibitors.
- Development of small molecule CDK12 inhibitors is needed to mimic siRNA effects.
Purpose of the Study:
- To design and synthesize potent and selective small molecule inhibitors of CDK12.
- To evaluate the efficacy and selectivity of novel CDK12 inhibitors.
Main Methods:
- Structure-based drug design and hybridization of existing compounds.
- Chemical synthesis and optimization of lead compounds.
- Kinase activity profiling, including selectivity panels and proteomics.
Main Results:
- A series of selective CDK12 inhibitors were developed, including compound 7.
- Compounds demonstrated selectivity against a broad kinase panel.
- Inhibition of RNA polymerase II Ser2 phosphorylation confirmed CDK12 activity.
- Selective compounds exhibited acute toxicity to OV90 and THP1 cells.
Conclusions:
- Novel small molecules selectively inhibit CDK12.
- These inhibitors reduce DNA-damage-response gene transcription.
- The developed compounds show potential as anti-cancer agents, particularly in combination therapies.
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