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.

Yan Li;Ya Chu;Guangjiang Shi;Xiaobin Wang;Wanli Ye;Chun Shan;Dajia Wang;Di Zhang;Wei He;Jingwei Jiang;Shuqian Ma;Yuhong Han;Zhili Zhao;Shijia Du;Zhen Chen;Zhiyu Li;Yong Yang;Chen Wang;Xi Xu;Hongxi Wu

Center for New Drug Safety Evaluation and Research,State Key Laboratory of Natural Medicines,China Pharmaceutical University,Nanjing 211198,China;School of Life Science and Technology,China Pharmaceutical University,Nanjing 211198,China;School of Pharmacy,China Pharmaceutical University,Nanjing 211198,China;Jiangsu Key Lab of Drug Screening,China Pharmaceutical University,Nanjing 211198,China

药学学报（英文版）

[1]Yan Li;Ya Chu;Guangjiang Shi;Xiaobin Wang;Wanli Ye;Chun Shan;Dajia Wang;Di Zhang;Wei He;Jingwei Jiang;Shuqian Ma;Yuhong Han;Zhili Zhao;Shijia Du;Zhen Chen;Zhiyu Li;Yong Yang;Chen Wang;Xi Xu;Hongxi Wu-.A novel inhibitor of ARfl and ARv7 induces protein degradation to overcome enzalutamide resistance in advanced prostate cancer)[J].药学学报（英文版）,2022(11):4165-4179

ARfl,ARv7,enzalutamide,Enzalutamide,ENZR,heterodimers

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