Janssen Research and Development, Spring House, Pennsylvania 19477, United States.
Janssen Research and Development, Turnhoutseweg 30, B-2340 Beerse, Belgium.
J Med Chem. 2021 Jan 28;64(2):909-924. doi: 10.1021/acs.jmedchem.0c01563. Epub 2021 Jan 20.
Persistent androgen receptor (AR) activation drives therapeutic resistance to second-generation AR pathway inhibitors and contributes to the progression of advanced prostate cancer. One resistance mechanism is point mutations in the ligand binding domain of AR that can transform antagonists into agonists. The AR F877L mutation, identified in patients treated with enzalutamide or apalutamide, confers resistance to both enzalutamide and apalutamide. Compound (JNJ-pan-AR) was identified as a pan-AR antagonist with potent activity against wild-type and clinically relevant AR mutations including F877L. Metabolite identification studies revealed a latent bioactivation pathway associated with . Subsequent lead optimization of led to amelioration of this pathway and nomination of (JNJ-63576253) as a clinical stage, next-generation AR antagonist for the treatment of castration-resistant prostate cancer (CRPC).
持续的雄激素受体 (AR) 激活导致对第二代 AR 通路抑制剂的治疗耐药，并促使晚期前列腺癌进展。一种耐药机制是 AR 配体结合域的点突变，可将拮抗剂转化为激动剂。在接受恩扎鲁胺或阿帕鲁胺治疗的患者中发现的 AR F877L 突变使恩扎鲁胺和阿帕鲁胺均产生耐药性。化合物 (JNJ-pan-AR) 被鉴定为一种 pan-AR 拮抗剂，对野生型和临床相关的 AR 突变（包括 F877L）具有强大的活性。代谢产物鉴定研究揭示了与 相关的潜在生物活化途径。随后对 的优化导致该途径得到改善，并将 （JNJ-63576253）选为治疗去势抵抗性前列腺癌 (CRPC) 的下一代 AR 拮抗剂进入临床阶段。
