A novel inhibitor of ARfl and ARv7 induces protein degradation to overcome enzalutamide resistance in advanced prostate cancer.
A novel inhibitor of ARfl and ARv7 induces protein degradation to overcome enzalutamide resistance in advanced prostate cancer.
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ARfl 和 ARv7 的新型抑制剂诱导蛋白质降解以克服晚期前列腺癌中的恩杂鲁胺耐药性
DOI：
10.1016/j.apsb.2022.05.003
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发表时间：
2022-11
影响因子：
14.5
通讯作者：
Wu, Hongxi
中科院分区：
文献类型：
--
作者：
Li, Yan;Chu, Ya;Shi, Guangjiang;Wang, Xiaobin;Ye, Wanli;Shan, Chun;Wang, Dajia;Zhang, Di;He, Wei;Jiang, Jingwei;Ma, Shuqian;Han, Yuhong;Zhao, Zhili;Du, Shijia;Chen, Zhen;Li, Zhiyu;Yang, Yong;Wang, Chen;Xu, Xi;Wu, Hongxi
关键词：
恩杂鲁胺 (ENZ) 是第二代雄激素受体 (AR) 拮抗剂，用于治疗去势抵抗性前列腺癌 (CRPC)，据报道可延长开始治疗后一年内的生存时间。然而，CRPC患者可能会出现ENZ耐药（ENZR），这主要是由AR信号传导异常重新激活驱动的，涉及全长AR（ARfl）或显性活性雄激素受体剪接变体7（ARv7）和ARfl/ARv7异二聚体的表达增加。目前对于 CRPC 中的 ENZR 尚无有效的治疗方法。在此，基于ENZ结构合理设计的小分子LLU-206对ARf1和组成型活性ARv7均表现出有效抑制作用，从而抑制PCa增殖并抑制CRPC中的ENZR。机械上，LLU-206通过小鼠双分钟2介导的泛素化促进ARfl/ARv7蛋白降解并减少ARfl/ARv7异二聚体。最后，LLU-206 表现出良好的药代动力学特性，但血脑屏障的渗透性较差，因此与基于 ENZ 的疗法相比，癫痫发作和神经毒性等不良反应的发生率较低。简而言之，我们的研究结果表明，LLU-206可以通过双靶向ARfl/ARv7异二聚体和蛋白质降解来有效抑制ARfl/ARv7驱动的CRPC，为新一代AR抑制剂的设计克服ARfl/ARv7驱动的CRPC提供新的见解。 LLU-206是一种新型ARfl/ARv7抑制剂，可通过ARfl/ARv7异二聚体和蛋白质降解的双重靶向来抑制PCa细胞增殖和ENZR肿瘤生长。
Enzalutamide (ENZ) is a second-generation androgen receptor (AR) antagonist used for the treatment of castration-resistant prostate cancer (CRPC) and reportedly prolongs survival time within a year of starting therapy. However, CRPC patients can develop ENZ resistance (ENZR), mainly driven by abnormal reactivation of AR signaling, involving increased expression of the full-length AR (ARfl) or dominantly active androgen receptor splice variant 7 (ARv7) and ARfl/ARv7 heterodimers. There is currently no efficient treatment for ENZR in CRPC. Herein, a small molecule LLU-206 was rationally designed based on the ENZ structure and exhibited potent inhibition of both ARfl and constitutively active ARv7 to inhibit PCa proliferation and suppress ENZR in CRPC. Mechanically, LLU-206 promoted ARfl/ARv7 protein degradation and decreased ARfl/ARv7 heterodimers through mouse double minute 2-mediated ubiquitination. Finally, LLU-206 exhibited favorable pharmacokinetic properties with poor permeability across the blood–brain barrier, leading to a lower prevalence of adverse effects, including seizure and neurotoxicity, than ENZ-based therapies. In a nutshell, our findings demonstrated that LLU-206 could effectively inhibit ARfl/ARv7-driven CRPC by dual-targeting of ARfl/ARv7 heterodimers and protein degradation, providing new insights for the design of new-generation AR inhibitors to overcome ARfl/ARv7-driven CRPC. LLU-206 is a novel ARfl/ARv7 inhibitor that can suppress PCa cell proliferation and ENZR tumor growth via dual-targeting of ARfl/ARv7 heterodimers and protein degradation.
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影响因子：
82.9
作者：
Chen, CD;Welsbie, DS;Sawyers, CL
通讯作者：
Sawyers, CL
影响因子：
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作者：
Liu C;Lou W;Yang JC;Liu L;Armstrong CM;Lombard AP;Zhao R;Noel ODV;Tepper CG;Chen HW;Dall'Era M;Evans CP;Gao AC
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Tubaro, Andrea
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作者：
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通讯作者：
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影响因子：
50.3
作者：
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通讯作者：
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