A structure-based virtual screening identifies a novel MDM2 antagonist in the activation of the p53 signaling and inhibition of tumor growth  

作　　者：Qing-yong Hu Lei Li Yu-huang Li Hai-bo Zhang Tao Deng Yang Liu Feng-tian Li Zhi-xiong Xiao Yang Cao 

机构地区：[1]Institute of Basic Medicine and Forensic Medicine,North Sichuan Medical College,Nanchong,637000,China [2]Center of Growth,Metabolism and Aging,Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education,College of Life Sciences,Sichuan University,Chengdu,610065,China [3]Animal Disease Prevention and Food Safety Key Laboratory of Sichuan Province,Microbiology and Metabolic Engineering Key Laboratory of Sichuan Province,Sichuan University,Chengdu,610065,China

出　　处：《Acta Pharmacologica Sinica》2025年第3期740-750,共11页中国药理学报(英文版)

基　　金：supported by the National Natural Science Foundation of China(Grant numbers 81973243,81861148031,81520108020 and 31401130).

摘　　要：p53,a tumor suppressor protein,has a vital role in the regulation of the cell cycle,apoptosis,and DNA damage repair.The degradation of p53 is predominantly controlled by the murine double minute 2(MDM2)protein,a ubiquitin E3 ligase.The overexpression or amplification of MDM2 is commonly observed in various human cancers bearing wild-type p53 alleles,leading to the rapid degradation of the p53 protein and the attenuation of p53 tumor suppression functions.Thus,a major effort in p53-based cancer therapy has been to research MDM2 antagonists that specifically stabilize and activate p53,leading to the suppression of tumor growth.However,despite numerous efforts to develop MDM2 antagonists,to date they have failed to reach clinical use,largely because of the cytotoxicity associated with these small molecules.This study used our newly designed structure-based virtual screening approach on a commercial compound library to identify a novel compound,CGMA-Q18,which directly binds to MDM2,leading to the activation of p53,the induction of apoptosis,and cell cycle arrest in cancer cells.Notably,CGMA-Q18 significantly inhibited tumor xenograft growth in nude mice without observable toxicity.These findings highlight our useful virtual screening protocol and CGMA-Q18 as a putative MDM2 antagonist.

关 键 词：MDM2 P53 virtual screening inhibitor 

分 类 号：R96[医药卫生—药理学] R730.2[医药卫生—药学]