Design, Synthesis, and Biological Evaluation of Potent and Selective PROTAC Degraders of Oncogenic KRAS<SUP>G12D</SUP>

doi:10.1021/acs.jmedchem.3c01622

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	Design, Synthesis, and Biological Evaluation of Potent and Selective PROTAC Degraders of Oncogenic KRAS^G12D
	Zhou, Chuan 1; Fan, Zisheng2,3,4 ; Gu, Yuejiao 1,5; Ge, Zhiming 5,6; Tao, Zhaofan 1,5; Cui, Rongrong 4; Li, Yupeng 7,8; Zhou, Guizhen2,3,4 ; Huo, Ruifeng 9; Gao, Mingshan 1; Wang, Dan 9; He, Wei 4,10; Zheng, Mingyue2,4,5,6 ; Zhang, Sulin 4; Xu, Tianfeng 1,5,6
	2024-01-10
发表期刊	JOURNAL OF MEDICINAL CHEMISTRY (IF:6.8[JCR-2023],7.1[5-Year])
ISSN	0022-2623
EISSN	1520-4804
卷号	67 期号:2
发表状态	已发表
DOI	10.1021/acs.jmedchem.3c01622
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.
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收录类别	SCI
语种	英语
资助项目	Youth Innovation Promotion Association of the Chinese Academy of Sciences[
WOS研究方向	Pharmacology & Pharmacy
WOS类目	Chemistry, Medicinal
WOS记录号	WOS:001151575400001
出版者	AMER CHEMICAL SOC
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/349930
专题	免疫化学研究所物质科学与技术学院生命科学与技术学院_博士生
共同第一作者	Fan, Zisheng; Gu, Yuejiao; Ge, Zhiming
通讯作者	Zheng, Mingyue; Zhang, Sulin; Xu, Tianfeng
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China 2.Shanghai Tech Univ, Shanghai Inst Adv Immunochem Studies, Sch Life Sci & Technol, Shanghai 201210, Peoples R China 3.Lingang Lab, Shanghai 200031, Peoples R China 4.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, State Key Lab Drug Res, Shanghai 201203, Peoples R China 5.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 6.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China 7.Univ Texas EI Paso, Sch Pharm, Dept Pharmaceut Sci, EI Paso, TX 79902 USA 8.Univ Texas EI Paso, Border Biomed Res Ctr, EI Paso, TX 79902 USA 9.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China 10.Nanchang Univ, Nanchang 330031, Peoples R China
通讯作者单位	免疫化学研究所
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 KRAS^G12D[J]. JOURNAL OF MEDICINAL CHEMISTRY,2024,67(2).
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 KRAS^G12D.JOURNAL OF MEDICINAL CHEMISTRY,67(2).
MLA	Zhou, Chuan,et al."Design, Synthesis, and Biological Evaluation of Potent and Selective PROTAC Degraders of Oncogenic KRAS^G12D".JOURNAL OF MEDICINAL CHEMISTRY 67.2(2024).