用选择性 CDK9 抑制剂调节前列腺癌中的雄激素受体驱动转录。
Modulating Androgen Receptor-Driven Transcription in Prostate Cancer with Selective CDK9 Inhibitors.
机构信息
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; MIT Center for Precision Cancer Medicine, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; MIT Center for Precision Cancer Medicine, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
出版信息
Cell Chem Biol. 2021 Feb 18;28(2):134-147.e14. doi: 10.1016/j.chembiol.2020.10.001. Epub 2020 Oct 20.
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）失去了对雄激素剥夺疗法的敏感性，但仍然依赖于雄激素受体（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，我们使用基于裂解物的小分子微阵列测定法，鉴定出 KI-ARv-03 是一种 AR 变体复合物结合物，可降低前列腺癌细胞中 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。进一步优化得到 KB-0742，这是一种口服生物利用度高、选择性的 CDK9 抑制剂，在 CRPC 模型中具有强大的抗肿瘤活性。在 22Rv1 细胞中，KB-0742 可迅速下调新生转录物，优先耗尽半衰期短的转录物和 AR 驱动的致癌程序。在体内，口服给予 KB-0742 可显著减少 CRPC 中的肿瘤生长，支持 CDK9 抑制作为一种有前途的治疗策略，以靶向 CRPC 中的 AR 依赖性。
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