State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China.
J Med Chem. 2023 Jul 27;66(14):9972-9991. doi: 10.1021/acs.jmedchem.3c00880. Epub 2023 Jul 17.
The androgen/androgen receptor (AR) signaling pathway plays an important role in castration-resistant prostate cancer (CRPC). Bifunctional agents that simultaneously degrade AR and inhibit androgen synthesis are expected to block the androgen/AR signaling pathway more thoroughly, demonstrating the promising therapeutic potential for CRPC, even enzalutamide-resistant CRPC. Herein, a series of steroid analogs were designed, synthesized, and identified as selective AR degraders, among which YXG-158 () was the most potent antitumor compound with dual functions of AR degradation and CYP17A1 inhibition. In addition, abrogated the hERG inhibition and exhibited excellent PK profiles. In vivo, effectively inhibited the growth of hormone-sensitive organs in the Hershberger assay and exhibited robust antitumor efficacy both in enzalutamide-sensitive (LNCaP/AR) and enzalutamide-resistant (C4-2b-ENZ) xenograft models. Thus, was chosen as a preclinical candidate for the treatment of enzalutamide-resistant prostate cancer.
雄激素/雄激素受体 (AR) 信号通路在去势抵抗性前列腺癌 (CRPC) 中发挥着重要作用。同时降解 AR 和抑制雄激素合成的双功能药物有望更彻底地阻断雄激素/AR 信号通路，为 CRPC（甚至是恩扎卢胺耐药的 CRPC）展示出有前景的治疗潜力。在此，设计、合成并鉴定了一系列甾体类似物，它们被鉴定为选择性 AR 降解剂，其中化合物 YXG-158 () 是最有效的具有双重功能的抗肿瘤化合物，具有 AR 降解和 CYP17A1 抑制作用。此外， 消除了 hERG 抑制作用，并表现出优异的 PK 特征。在体内， 在 Hershberger 测定中有效抑制了激素敏感器官的生长，并在恩扎卢胺敏感（LNCaP/AR）和恩扎卢胺耐药（C4-2b-ENZ）异种移植模型中均表现出强大的抗肿瘤功效。因此， 被选为治疗恩扎卢胺耐药性前列腺癌的临床前候选药物。
