A naturally derived small molecule compound suppresses tumor growth and metastasis in mice by relieving p53-dependent repression of CDK2/Rb signaling and the Snail-driven EMT

作     者：REN Boxue LI Yang DI Lei CHENG Ranran LIU Lijuan LI Hongmei LI Yi TANG Zhangrui YAN Yongming LU Tao FU Rong CHENG Yongxian WU Zhaoqiu 

作者机构：State Key Laboratory of Natural MedicinesDepartment of PharmacologySchool of PharmacyChina Pharmaceutical UniversityNanjing 211198China Institute for Inheritance-Based Innovation of Chinese MedicineSchool of Pharmaceutical SciencesShenzhen University Health Science CenterShenzhen 518060China 

出 版 物：《Chinese Journal of Natural Medicines》 (中国天然药物（英文版）)

年 卷 期：2024年第22卷第2期

页      面：112-126页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 1006[医学-中西医结合] 100706[医学-药理学] 1002[医学-临床医学] 100602[医学-中西医结合临床] 10[医学] 

基　　金：supported by the National Natural Science Foundation of China(Nos.82125036,82273964,81973363,82304538,81973188) the State Key Laboratory of Natural Medicines of CPU(No.SKLNMZZ202207) the“Double-First Class”Program of CPU,the National Key Research and Development Program of China(No.2017YFA0503900) the Jiangsu Provincial Natural Science Fund for Distinguished Young Scholar(No.BK20230042) the Jiangsu Funding Program for Excellent Postdoctoral Talent(No.2023ZB171) the Shenzhen Fundamental Research Program(No.JCYJ20200109114225087) 

主　　题：LZ22 Wild-type p53 p53 Reactivator Snail-driven EMT Tumor growth and metastasis 

摘      要：The tumor suppressor protein p53 is central to cancer biology,with its pathway reactivation emerging as a promising therapeutic strategy in *** study introduced LZ22,a novel compound that selectively inhibits the growth,migration,and metastasis of tumor cells expressing wild-type p53,demonstrating ineffectiveness in cells devoid of p53 or those expressing mutant ***22’s mechanism of action involves a high-affinity interaction with the histidine-96 pocket of the MDM2 *** interaction disrupted the MDM2-p53 binding,consequently stabilizing p53 by shielding it from proteasomal ***22 impeded cell cycle progression and diminished cell proliferation by reinstating the p53-dependent suppression of the CDK2/Rb signaling ***,LZ22 alleviated the p53-dependent repression of Snail transcription factor expression and its consequent EMT,effectively reducing tumor cell migration and distal ***,LZ22 administration in tumor-bearing mice did not manifest notable side *** findings position LZ22 as a structurally unique reactivator of p53,offering therapeutic promise for the management of human cancers with wild-type TP53.