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Discovery of an Efficacious RET PROTAC Degrader with Enhanced Antiproliferative Activity against Resistant Cancer Cells Harboring RET Solvent-Front Mutations

文献类型：期刊论文

作者Zhang, Qian4; He, Yingqi3,5; Rao, Danni1,2; He, Rui3,5; Yu, Lei6; Sun, Yaoliang2; Lai, Yuanhui7; Shi, Zihan1,2; Peng, Lijie3,5; Zhang, Zhang3,5,7
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2024-12-28
卷号68期号:1页码:753-775
ISSN号0022-2623
DOI10.1021/acs.jmedchem.4c02692
通讯作者Zhang, Zhang(zzmoxue@163.com) ; Xu, Shilin(slxu@simm.ac.cn)
英文摘要Rearranged during transfection (RET) kinase is a validated therapeutic target for various cancers characterized by RET alterations. Although two selective RET inhibitors, selpercatinib and pralsetinib, have been approved by the FDA, acquired resistance through solvent-front mutations has been identified rapidly. Developing proteolysis targeting chimera (PROTAC) targeting RET mutations offers a promising strategy to combat drug resistance. Herein, we describe the design, synthesis, and evaluation of a series of RET PROTAC degraders. The representative compound QZ2135 (20) effectively degraded RET kinase and its resistant mutants, such as V804M and G810C/R. It also exhibited superior antiproliferative activity against Ba/F3 cells stably expressing oncogenic fusions of RET with solvent-front mutants, including G810C/R/S, compared to its parental inhibitor. Notably, QZ2135 demonstrated in vivo antitumor efficacy in a Ba/F3-KIF5B-RET-G810C xenograft mouse model. Together, this study provides a potential alternative strategy for overcoming acquired resistance to RET inhibitors mediated by solvent-front mutations.
WOS关键词TARGETING RET ; ACQUIRED-RESISTANCE ; POTENT ; INHIBITOR ; DISEASE
资助项目National Natural Science Foundation of China[22277128] ; National Natural Science Foundation of China[22307132] ; National Natural Science Foundation of China[82103973] ; National Natural Science Foundation of China[2023YFA1800804] ; National Key Research and Development Program of China[2024A1515012557] ; Natural Science Foundation of Guangdong Province[2024B1515040007] ; Guangdong Basic and Applied Basic Research Foundation[2024B03J1243] ; Guangzhou Municipal Science and Technology Bureau
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001387080300001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/315297]  
专题中国科学院上海药物研究所
通讯作者Zhang, Zhang; Xu, Shilin
作者单位1.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, Shanghai 201203, Peoples R China
3.Jinan Univ, Sch Pharm, Guangdong Basic Res Ctr Excellence Nat Bioact Mol, State Key Lab Bioact Mol & Druggabil Assessment, Guangzhou 510632, Peoples R China
4.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
5.Jinan Univ, Sch Pharm, Int Cooperat Lab Tradit Chinese Med Modernizat & I, Guangzhou City Key Lab Precis Chem Drug Dev,Minist, Guangzhou 510632, Peoples R China
6.Tongji Univ, Canc Ctr, Shanghai Peoples Hosp 10, Sch Med, Shanghai 200092, Peoples R China
7.Jinan Univ, Guangdong Prov Gen Hosp 2, Dept Thyroid & Breast Surg, Guangzhou 510310, Peoples R China
8.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
推荐引用方式
GB/T 7714		 Zhang, Qian,He, Yingqi,Rao, Danni,et al. Discovery of an Efficacious RET PROTAC Degrader with Enhanced Antiproliferative Activity against Resistant Cancer Cells Harboring RET Solvent-Front Mutations[J]. JOURNAL OF MEDICINAL CHEMISTRY,2024,68(1):753-775.
APA Zhang, Qian.,He, Yingqi.,Rao, Danni.,He, Rui.,Yu, Lei.,...&Xu, Shilin.(2024).Discovery of an Efficacious RET PROTAC Degrader with Enhanced Antiproliferative Activity against Resistant Cancer Cells Harboring RET Solvent-Front Mutations.JOURNAL OF MEDICINAL CHEMISTRY,68(1),753-775.
MLA Zhang, Qian,et al."Discovery of an Efficacious RET PROTAC Degrader with Enhanced Antiproliferative Activity against Resistant Cancer Cells Harboring RET Solvent-Front Mutations".JOURNAL OF MEDICINAL CHEMISTRY 68.1(2024):753-775.

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来源：上海药物研究所

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