Structure-Based Design and Synthesis of Potent and Selective KRAS G12D Inhibitors

被引：4

作者：

Cheng, Hengmiao ^{[1
]}

Li, Puhui ^{[1
]}

Chen, Ping ^{[1
]}

Irimia, Adriana ^{[1
]}

Bae, Jae Hyun ^{[1
]}

Brooun, Alexei ^{[1
]}

Fagan, Patrick ^{[1
]}

Lam, Richard ^{[1
]}

Lin, Bingzhen ^{[1
]}

Zhang, Jingchuan ^{[1
]}

Zhan, Xuejun ^{[2
]}

Wu, Xu ^{[2
]}

Xie, Nan ^{[3
]}

Chiang, Gary ^{[1
]}

Shoemaker, Robert ^{[1
]}

Vernier, Jean-Michel ^{[1
]}

机构：

[1] Erasca Inc, San Diego, CA 92121 USA

[2] Wuxi AppTec Wuhan Co Ltd, Wuhan 430075, Hubei, Peoples R China

[3] Wuxi AppTec Shanghai Co Ltd, Shanghai 200131, Peoples R China

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2023年 / 14卷 / 10期

关键词：

KRAS; G12D selective inhibitor; ERAS-5024; SBDD; PDAC; anti-tumor efficacy;

D O I：

10.1021/acsmedchemlett.3c00245

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

KRAS G12D mutation has been found in approximately 45% of pancreatic ductal adeno-carcinoma (PDAC) cases, making it an attractive therapeutic target. Through structure-based drug design, a series of potent and selective KRAS G12D inhibitors were designed. The lead compound, ERAS-5024, inhibited ERK1/2 phosphorylation and cell proliferation in three-dimensional Cell-Titer Glo assays in AsPC-1 PDAC cells with single-digit nanomolar potency and caused tumor regression in the in vivo efficacy studies. We describe here the details of the design and synthesis program that led to the discovery of ERAS-5024.

引用

页码：1351 / 1357

页数：7

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