Journal
CELL CHEMICAL BIOLOGY
Volume 28, Issue 2, Pages 134-+Publisher
CELL PRESS
DOI: 10.1016/j.chembiol.2020.10.001
Keywords
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Categories
Funding
- Koch Institute-Dana-Farber/Harvard Cancer Center Bridge Project [P30-CA14051]
- Royal G. and Mae H. Westaway Family Memorial Fund
- Ono Pharma Foundation
- MIT Center for Precision Cancer Medicine
- NIH/NCI [P01 CA163227, P50 CA090381]
- Janssen Pharmaceuticals, Inc., via the Transcend partnership
- Cancer Prevention Research Institute of Texas [RR150093]
- NIH
- NCI [1R01CA215452-01]
- Pew-Stewart Scholar for Cancer Research
- German Research Foundation (DFG Postdoctoral Research Fellowship) [RI 2670/1-1]
- National Science Foundation Graduate Research Fellowship [1122374]
- Ludwig Center at MIT's Koch Institute
- GSK-MIT Gertrude B. Elion Research Fellowship Program for Drug Discovery and Disease
- Ludwig Center at MIT's Koch institute [1097737]
- AbbVie [1097737]
- Bayer Pharma AG
- Boehringer Ingelheim
- Canada Foundation for Innovation
- Eshelman Institute for Innovation
- Genome Canada
- Innovative Medicines Initiative EUbOPEN [875510]
- Janssen
- Merck KGaA Darmstadt Germany
- MSD
- Novartis Pharma AG
- Ontario Ministry of Economic Development and Innovation
- Pfizer
- Sao Paulo Research Foundation-FAPESP
- Takeda
- Wellcome
- German Cancer Network (DKTK)
- Frankfurt Cancer Center
- Prostate Cancer Foundation Young Investigator Award [18YOUN24]
- Department of Defense, CDMRP, PCRP Early Investigator Award [W81XWH-17PCRP-EIRA, PC170570]
- CDMRP [PC170570, 1101000] Funding Source: Federal RePORTER
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By targeting CDK9, the inhibitors KI-ARv-03 and KB-0742 show potent anti-tumor activity in CRPC models, reducing transcription and proliferation in prostate cancer cells. These findings suggest CDK9 inhibition as a promising therapeutic strategy for targeting AR dependence in CRPC.
Castration-resistant prostate cancers (CRPCs) lose sensitivity to androgen-deprivation therapies but frequently remain dependent on oncogenic transcription driven by the androgen receptor (AR) and its splice variants. To discover modulators of AR-variant activity, we used a lysate-based small-molecule microarray assay and identified KI-ARv-03 as an AR-variant complex binder that reduces AR-driven transcription and proliferation in prostate cancer cells. We deduced KI-ARv-03 to be a potent, selective inhibitor of CDK9, an important cofactor for AR, MYC, and other oncogenic transcription factors. Further optimization resulted in KB-0742, an orally bioavailable, selective CDK9 inhibitor with potent anti-tumor activity in CRPC models. In 22Rv1 cells, KB-0742 rapidly downregulates nascent transcription, preferentially depleting short half-life transcripts and AR-driven oncogenic programs. In vivo, oral administration of KB-0742 significantly reduced tumor growth in CRPC, supporting CDK9 inhibition as a promising therapeutic strategy to target AR dependence in CRPC.
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