|Publication Type||Journal Article|
|Year of Publication||2021|
|Authors||Richters, A, Doyle, SK, Freeman, DB, Lee, C, Leifer, BS, Jagannathan, S, Kabinger, F, Koren, JVrabič, 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, B Trotter, W, Saffran, DC, Bischofberger, N, Knapp, S, Russo, JW, Hickson, I, Bischoff, JR, Gottardis, MM, Balk, SP, Lin, CY, Pop, MS, Koehler, AN|
|Journal||Cell Chem Biol|
|Date Published||2021 Feb 18|
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.
|Alternate Journal||Cell Chem Biol|