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

• Published in: ACS medicinal chemistry letters Vol. 14; no. 10; pp. 1351 - 1357
• Main Authors: Cheng, Hengmiao, Li, Puhui, Chen, Ping, Irimia, Adriana, Bae, Jae Hyun, Brooun, Alexei, Fagan, Patrick, Lam, Richard, Lin, Bingzhen, Zhang, Jingchuan, Zhan, Xuejun, Wu, Xu, Xie, Nan, Chiang, Gary, Shoemaker, Robert, Vernier, Jean-Michel
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 12-10-2023
• Subjects: Letter; SBDD; KRAS; PDAC; G12D selective inhibitor; ERAS-5024; anti-tumor efficacy
• ISSN: 1948-5875; 1948-5875
• DOI: 10.1021/acsmedchemlett.3c00245

KRAS G12D mutation has been found in approximately 45% of pancreatic ductal adeno­carcinoma (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.