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Design, Synthesis, and Biological Evaluation of Potent and Selective PROTAC Degraders of Oncogenic KRASG12D

文献类型：期刊论文

作者Zhou, Chuan10; Fan, Zisheng7,8,9; Gu, Yuejiao6,10; Ge, Zhiming5,6; Tao, Zhaofan6,10; Cui, Rongrong7; Li, Yupeng3,4; Zhou, Guizhen7,8,9; Huo, Ruifeng1; Gao, Mingshan10
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2024-01-10
卷号67期号:2页码:1147-1167
ISSN号0022-2623
DOI10.1021/acs.jmedchem.3c01622
通讯作者Zheng, Mingyue(myzheng@simm.ac.cn) ; Zhang, Sulin(slzhang@simm.ac.cn) ; Xu, Tianfeng(tfxu@simm.ac.cn)
英文摘要KRAS(G12D), the most frequent KRAS oncogenic mutation, is a promising target for cancer therapy. Herein, we report the design, synthesis, and biological evaluation of a series of KRAS(G12D) PROTACs by connecting the analogues of MRTX1133 and the VHL ligand. Structural modifications of the linker moiety and KRAS inhibitor part suggested a critical role of membrane permeability in the degradation activity of the KRAS(G12D) PROTACs. Mechanism studies with the representative compound 8o demonstrated that the potent, rapid, and selective degradation of KRAS(G12D) induced by 8o was via a VHL- and proteasome-dependent manner. This compound selectively and potently suppressed the growth of multiple KRAS(G12D )mutant cancer cells, displayed favorable pharmacokinetic and pharmacodynamic properties in mice, and showed significant antitumor efficacy in the AsPC-1 xenograft mouse model. Further optimization of 8o appears to be promising for the development of a new chemotherapy for KRAS(G12D)-driven cancers as the complementary therapeutic strategy to KRAS inhibition.
WOS关键词INDUCED PROTEIN-DEGRADATION ; SIGNALING PATHWAYS ; RAS ONCOGENES ; DISCOVERY ; CANCER ; KERATINS ; GTPASES
资助项目Youth Innovation Promotion Association of the Chinese Academy of Sciences[22107110] ; Youth Innovation Promotion Association of the Chinese Academy of Sciences[T2225002] ; National Natural Science Foundation of China[2023296] ; Youth Innovation Promotion Association CAS
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001151575400001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/308960]  
专题新药研究国家重点实验室
通讯作者Zheng, Mingyue; Zhang, Sulin; Xu, Tianfeng
作者单位1.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
2.Nanchang Univ, Nanchang 330031, Peoples R China
3.Univ Texas EI Paso, Border Biomed Res Ctr, EI Paso, TX 79902 USA
4.Univ Texas EI Paso, Sch Pharm, Dept Pharmaceut Sci, EI Paso, TX 79902 USA
5.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
6.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
7.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, State Key Lab Drug Res, Shanghai 201203, Peoples R China
8.Lingang Lab, Shanghai 200031, Peoples R China
9.Shanghai Tech Univ, Shanghai Inst Adv Immunochem Studies, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
10.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Zhou, Chuan,Fan, Zisheng,Gu, Yuejiao,et al. Design, Synthesis, and Biological Evaluation of Potent and Selective PROTAC Degraders of Oncogenic KRASG12D[J]. JOURNAL OF MEDICINAL CHEMISTRY,2024,67(2):1147-1167.
APA Zhou, Chuan.,Fan, Zisheng.,Gu, Yuejiao.,Ge, Zhiming.,Tao, Zhaofan.,...&Xu, Tianfeng.(2024).Design, Synthesis, and Biological Evaluation of Potent and Selective PROTAC Degraders of Oncogenic KRASG12D.JOURNAL OF MEDICINAL CHEMISTRY,67(2),1147-1167.
MLA Zhou, Chuan,et al."Design, Synthesis, and Biological Evaluation of Potent and Selective PROTAC Degraders of Oncogenic KRASG12D".JOURNAL OF MEDICINAL CHEMISTRY 67.2(2024):1147-1167.

入库方式： OAI收割

来源：上海药物研究所

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