Homo-PROTAC mediated suicide of MDM2 to treat non-small cell lung cancer

作     者：Shipeng He Junhui Ma Yuxin Fang Ying Liu Shanchao Wu Guoqiang Dong Wei Wang Chunquan Sheng Shipeng He;Junhui Ma;Yuxin Fang;Ying Liu;Shanchao Wu;Guoqiang Dong;Wei Wang;Chunquan Sheng

作者机构：Institute of Translational MedicineShanghai UniversityShanghai 200444China School of PharmacySecond Military Medical UniversityShanghai 200433China Department of Pharmacology and Toxicology and BIO5 InstituteUniversity of ArizonaTucsonAZ 85721USA School of MedicineTongji UniversityShanghai 200072China 

出 版 物：《Acta Pharmaceutica Sinica B》 (药学学报（英文版）)

年 卷 期：2021年第11卷第6期

页      面：1617-1628页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 1004[医学-公共卫生与预防医学(可授医学、理学学位)] 1002[医学-临床医学] 1001[医学-基础医学(可授医学、理学学位)] 100214[医学-肿瘤学] 10[医学] 

基　　金：supported by National Natural Science Foundation of China (Grant Nos. 82030105, 21738002 and 21807113) the National Key R&D Program of China (Grant No. 2020YFA0509100) the Innovation Program of Shanghai Municipal Education Commission (Grant No. 2019-01-07-00-07E00073, China)。 

主　　题：Homo-PROTAC MDM2 Self-degradation In vivo antitumor activity 

摘      要：The dose-related adverse effects of MDM2-P5 3 inhibitors have caused significant concern in the development of clinical safe anticancer agents.Herein we report an unprecedented homo-PROTAC strategy for more effective disruption of MDM2-P53 interaction.The design concept is inspired by the capacity of sub-stoichiometric catalytic PROTACs enabling to degrade an unwanted protein and the dual functions of MDM2 as an E3 ubiquitin ligase and a binding protein with tumor suppressor P53.The new homo-PROTACs are designed to induce self-degradation of MDM2.The results of the investigation have shown that PROTAC 11 a efficiently dimerizes MDM2 with highly competitive binding activity and induces proteasome-dependent self-degradation of MDM2 in A549 non-small cell lung cancer cells.Furthermore,markedly,enantiomer 11 a-1 exhibits potent in vivo antitumor activity in A549 xenograft nude mouse model,which is the first example of homo-PROTAC with in vivo therapeutic potency.This study demonstrates the potential of the homo-PROTAC as an alternative chemical tool for tumorigenic MDM2 knockdown,which could be developed into a safe therapy for cancer treatment.