State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China.
Department of Pharmacy, Shanxi Medical University, Taiyuan, Xinjian Road 56, 030001, China.
Eur J Med Chem. 2019 Nov 15;182:111608. doi: 10.1016/j.ejmech.2019.111608. Epub 2019 Aug 10.
Androgen receptor (AR) has been a target of prostate cancer (PC) for nearly six decades. Recently, downregulating or degrading AR and the mutants especially the splice variant 7 (AR-V7) lacking ligand binding domain (LBD) emerged as an advantageous therapeutic approach to overcome drug resistance. Here, the structural modification of darolutamide resulted in the discovery of dual-action AR inhibitors and down-regulators. Unlike other traditional AR antagonists targeting the AR-LBD, compounds 4k and 4b not only inhibit the activities of wt-AR and AR-F876L mutant but also downregulate the protein expression of full-length (AR-full) and AR variant 7 (AR-V7) at mRNA level. In cell proliferation assays, compounds 4k and 4b exhibited better antiproliferative activities than darolutamide and enzalutamide against AR-V7-positive 22Rv1 cells and VCaP cells. In addition, 4k demonstrated better antitumor activity than clinically used enzalutamide in castration-resistant VCaP xenograft model. Collectively, combining the activities of AR inhibition and downregulation, compound 4k is proposed as an advantageous lead compound to disrupt AR signaling and overcome resistance.
雄激素受体（AR）一直是前列腺癌（PC）近六十年的靶点。最近，下调或降解 AR 和突变体，特别是缺乏配体结合域（LBD）的剪接变体 7（AR-V7），成为克服耐药性的有利治疗方法。在这里，对达罗他胺进行结构修饰，发现了双重作用的 AR 抑制剂和下调剂。与其他靶向 AR-LBD 的传统 AR 拮抗剂不同，化合物 4k 和 4b 不仅抑制 wt-AR 和 AR-F876L 突变体的活性，而且还在 mRNA 水平下调全长（AR-full）和 AR 变体 7（AR-V7）的蛋白表达。在细胞增殖试验中，化合物 4k 和 4b 对 AR-V7 阳性 22Rv1 细胞和 VCaP 细胞的增殖活性优于达罗他胺和恩扎鲁胺。此外，4k 在去势抵抗性 VCaP 异种移植模型中显示出比临床使用的恩扎鲁胺更好的抗肿瘤活性。总的来说，化合物 4k 结合了 AR 抑制和下调的活性，被提议作为一种有优势的先导化合物，以破坏 AR 信号并克服耐药性。
