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.

去势抵抗性前列腺癌 (CRPC) 对雄激素剥夺疗法失去敏感性，但通常仍依赖于由雄激素受体 (AR) 及其剪接变体驱动的致癌转录。为了发现 AR 变体活性的调节剂，我们使用了基于裂解物的小分子微阵列分析，并将KI-ARv-03鉴定为 AR 变体复合物结合剂，可减少前列腺癌细胞中 AR 驱动的转录和增殖。我们推断KI-ARv-03是 CDK9 的有效选择性抑制剂，CDK9 是 AR、MYC 和其他致癌转录因子的重要辅助因子。进一步优化产生了KB-0742，这是一种口服生物可利用的选择性 CDK9 抑制剂，在 CRPC 模型中具有有效的抗肿瘤活性。在 22Rv1 细胞中，KB-0742迅速下调新生转录，优先消耗短半衰期转录本和 AR 驱动的致癌程序。在体内，KB-0742 的口服给药显着降低了 CRPC 中的肿瘤生长，支持 CDK9 抑制作为靶向 CRPC 中 AR 依赖性的有前途的治疗策略。