Discovery of a highly potent and orally available importin-β1 inhibitor that overcomes enzalutamide-resistance in advanced prostate cancer  

作　　者：Jia-Luo Huang Xue-Long Yan Dong Huang Lu Gan Huahua Gao Run-Zhu Fan Shen Li Fang-Yu Yuan Xinying Zhu Gui-Hua Tang Hong-Wu Chen Junjian Wang Sheng Yin 

机构地区：[1]School of Pharmaceutical Sciences,Sun Yat-sen University,Guangzhou 510006,China [2]School of Pharmacy,Guizhou Medical University,Guian New District,Guizhou 550025,China [3]School of Medicine,University of California Davis,Sacramento,CA 95817,USA

出　　处：《Acta Pharmaceutica Sinica B》2023年第12期4934-4944,共11页药学学报（英文版）

基　　金：supported by the Natural Science Foundation of China(Nos.82273804,81973195,81872891,and 81973203);the Southerm Marine Science and Engineering Guangdong Laboratory(Zhuhai)(No.SML2021SP301,China);Open Program of Shenzhen Bay Laboratory(No.SZBL2021080601007,China);the Guangdong Natural Science Funds for Distinguished Young Scholar(No.2019B151502016,China);Guangdong-Hong Kong-Macao research team project of the Guangdong Basic and Applied Basic Research Foundation(No.2022B1515130008,China).

摘　　要：Nuclear transporter importin-β1 is emerging as an attractive target by virtue of its prevalence in many cancers.However,the lack of druggable inhibitors restricts its therapeutic proof of concept.In the present work,we optimized a natural importin-β1 inhibitor DD1 to afford an improved analog DD1-Br with better tolerability(>25 folds)and oral bioavailability.DD1-Br inhibited the survival of castration-resistant prostate cancer(CRPC)cells with sub-nanomolar potency and completely prevented tumor growth in resistant CRPC models both in monotherapy(0.5 mg/kg)and in enzalutamidecombination therapy.Mechanistic study revealed that by targeting importin-β1,DD1-Br markedly inhibited the nuclear accumulation of multiple CRPC drivers,particularly AR-V7,a main contributor to enzalutamide resistance,leading to the integral suppression of downstream oncogenic signaling.This study provides a promising lead for CRPC and demonstrates the potential of overcoming drug resistance in advanced CRPC via targeting importin-β1.

关 键 词：Importin-β1 CRPC Drug discovery Enzalutamide-resistance Natural product Cancer Daphnane diterpenoid Nuclear transporter 

分 类 号：R73[医药卫生—肿瘤]