Abstract LB197: VS-7375, a non-covalent dual ON/OFF KRASG12D inhibitor, displays superior activity to ON-only KRASG12D inhibitors in preclinical models of pancreatic cancer

作者：Brandon L. Mouery, Clint A. Stalnecker, Adrienne D. Cox, Silvia Coma, Jonathan A. Pachter, Channing J. Der · 发表于：Cancer Research · 年份：2026 · DOI：10.1158/1538-7445.am2026-lb197 · 被引用次数：1 · 研究领域：Protein Kinase Regulation and GTPase Signaling、HER2/EGFR in Cancer Research、14-3-3 protein interactions

Abstract The FDA approval of two selective OFF-state KRASG12C inhibitors has stimulated comprehensive development of mechanistically distinct inhibitors of additional KRAS mutations. In particular, approximately 20 selective KRASG12D inhibitors are currently in clinical evaluation. Their mechanisms of action include both ON- and OFF-state inhibitors and both covalent and non-covalent inhibitors. Here we compared the activity of VS-7375 (GFH375), a non-covalent dual ON/OFF KRASG12D inhibitor, with the covalent ON-only KRASG12D inhibitor zoldonrasib (RMC-9805). We found that VS-7375 exhibited greater anti-proliferative potency than RMC-9805 in a panel of KRASG12D-mutant pancreatic ductal adenocarcinoma (PDAC) cell lines. VS-7375 was 40-fold less potent in the KRASG12C cell line MIA PaCa-2, indicating high selectivity for KRASG12D. Furthermore, VS-7375 showed near complete inhibition of phosphorylated ERK (pERK) at concentrations as low as 1 nM by 4 hours, which persisted for up to 48 hours, whereas incomplete suppression of pERK was observed with as high as 30 nM of RMC-9805 by 4 hours. RMC-9805 suppressed pERK by 24 hours but required concentrations 10-30x higher than VS-7375 and rebounded by 48 hours. Similarly, we found that VS-7375 exhibited greater potency than RMC-9805 in suppressing phosphorylated AKT and S6, and MYC expression levels. To further compare the durability of inhibition, we performed washout experiments monitoring signaling inhibition after removal of drug. ...