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Ref Type Journal Article
PMID (33086052)
Authors Richters A, Doyle SK, Freeman DB, Lee C, Leifer BS, Jagannathan S, Kabinger F, Koren JV, Struntz NB, Urgiles J, Stagg RA, Curtin BH, Chatterjee D, Mathea S, Mikochik PJ, Hopkins TD, Gao H, Branch JR, Xin H, Westover L, Bignan GC, Rupnow BA, Karlin KL, Olson CM, Westbrook TF, Vacca J, Wilfong CM, Trotter BW, Saffran DC, Bischofberger N, Knapp S, Russo JW, Hickson I, Bischoff JR, Gottardis MM, Balk SP, Lin CY, Pop MS, Koehler AN
Title Modulating Androgen Receptor-Driven Transcription in Prostate Cancer with Selective CDK9 Inhibitors.
Journal Vol Issue Date Pages Journal Short Title
Cell chemical biology 28 2 2021 Feb 18 134-147.e14 Cell Chem Biol
URL
Abstract Text 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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
KB-0742 KB-0742 0 1
Drug Name Trade Name Synonyms Drug Classes Drug Description
KB-0742 KB0742|KB 0742 CDK9 Inhibitor 21 KB-0742 is a CDK9 inhibitor, which may result in reduced Cdk9-mediated transcriptional activity, apoptotic induction, and inhibition of tumor growth (PMID: 33086052).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References