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

被引：8

作者：

Zhou, Chuan ^{[1
]}

Fan, Zisheng ^{[2
,3
,4
]}

Gu, Yuejiao ^{[1
,5
]}

Ge, Zhiming ^{[5
,6
]}

Tao, Zhaofan ^{[1
,5
]}

Cui, Rongrong ^{[4
]}

Li, Yupeng ^{[7
,8
]}

Zhou, Guizhen ^{[2
,3
,4
]}

Huo, Ruifeng ^{[9
]}

Gao, Mingshan ^{[1
]}

Wang, Dan ^{[9
]}

He, Wei ^{[4
,10
]}

Zheng, Mingyue ^{[2
,4
,5
,6
]}

Zhang, Sulin ^{[4
]}

Xu, Tianfeng ^{[1
,5
,6
]}

机构：

[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

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2024年 / 67卷 / 02期

基金：

中国国家自然科学基金;

关键词：

INDUCED PROTEIN-DEGRADATION; SIGNALING PATHWAYS; RAS ONCOGENES; DISCOVERY; CANCER; KERATINS; GTPASES;

D O I：

10.1021/acs.jmedchem.3c01622

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

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.

引用

页码：1147 / 1167

页数：21

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