Activating mutations in the KRAS GTPase are frequently detected in multiple malignancies and are known to be oncogenic drivers. In particular, the glycine to cysteine substitution at codon 12 of KRAS (KRASG12C) is observed in non-small cell lung cancer (NSCLC) and colorectal cancer, which represent areas of high unmet medical need. Covalent engagement of this mutant cysteine with small molecules induces a druggable pocket in KRAS that locks the GTPase into an inactive GDP-bound conformation. In 2021, The U.S. Food and Drug Administration approved LumakrasTM (sotorasib) as the first therapy to covalently target KRASG12C for the treatment of NSCLC, and multiple additional covalent KRASG12C inhibitors are advancing in clinical trials, including adagrasib (MRTX849). We optimized a novel series of mutant-selective KRASG12C quinazoline-based covalent inhibitors demonstrating high potency in a biochemical target engagement assay and pERK inhibition in NSCLC H358 cells. We will discuss SAR, parallel optimization of both potency and physicochemical properties, as well as in vivo efficacy and pharmacokinetic/pharmacodynamic markers assessment in tumor xenograft models.

Identification of quinazoline-based covalent inhibitors of KRASG12C for the treatment of solid tumors

Fall 2022 abstracts, posters, and presentations will launch in mid-September.

ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.