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. H...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.展开更多
基金supported by the National Natural Science Foundation of China (Nos. 81903656 and 81673468)the National Key New Drug Innovation Program, the Ministry of Science and Technology of China (No. 2018ZX09201017-006)+3 种基金Natural Science Foundation of Jiangsu Province (No. BK20180560, China)China Postdoctoral Science Foundation (No. 2018M632430)“Double First-Class” University project (Nos. CPU2018GF10 and CPU2018GY46, China)the Scientific Startup Foundation for High level Scientists of China Pharmaceutical University (No. 3154070026, China)
文摘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.
