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,...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.展开更多
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)+2 种基金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).
文摘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.
