State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China.
Department of Hepatobiliary Pancreatic Surgery, Henan Province People's Hospital, Zhengzhou, 450003, China.
Eur J Med Chem. 2019 Jun 1;171:265-281. doi: 10.1016/j.ejmech.2019.03.041. Epub 2019 Mar 22.
Prostate cancer (PC) is the second most common malignancy in men worldwide. Among current therapies, two antiandrogens, Abiraterone Acetate and Enzalutamide (Enza) have become the standard of care for patients with metastatic castration-resistant prostate cancer (mCRPC). Here, we designed and synthesized a new series of nonsteroidal compounds deriving from the hybridization of Abiraterone (Abi) and Enzalutamide, among which compound 4a featuring the diphenylamine scaffold was identified as a potent and cell selective androgen receptor (AR) antagonist. In cell proliferation assays, compound 4a exhibited better antiproliferative activities than Enzalutamide against AR-overexpressing VCaP cells and 22Rv1 cells bearing H874Y-mutated AR. In addition, 4a suppressed the activity of AR-F876L mutant that confers resistance to Enzalutamide and efficiently blocked R1881-induced PSA and FKBP5 gene expression. In competitive binding assay, compound 4a displayed higher binding affinity to AR than Enzalutamide. These results suggest compound 4a as a potential candidate to treat Enza-resistant CRPC.
前列腺癌（PC）是全球男性中第二常见的恶性肿瘤。在当前的治疗方法中，两种抗雄激素药物，醋酸阿比特龙和恩扎鲁胺（Enza）已成为转移性去势抵抗性前列腺癌（mCRPC）患者的标准治疗方法。在这里，我们设计并合成了一系列源自阿比特龙（Abi）和恩扎鲁胺杂交的非甾体化合物，其中具有二苯胺支架的化合物 4a 被鉴定为有效的细胞选择性雄激素受体（AR）拮抗剂。在细胞增殖测定中，化合物 4a 对 AR 过表达的 VCaP 细胞和携带 H874Y 突变 AR 的 22Rv1 细胞表现出比恩扎鲁胺更好的抗增殖活性。此外，4a 抑制了赋予对恩扎鲁胺耐药性的 AR-F876L 突变体的活性，并有效阻断了 R1881 诱导的 PSA 和 FKBP5 基因表达。在竞争性结合测定中，化合物 4a 对 AR 的结合亲和力高于恩扎鲁胺。这些结果表明化合物 4a 是治疗恩扎鲁胺耐药性 CRPC 的潜在候选药物。
