kras g12cin1

K-Ras G12C-IN-1 is a novel, irreversible inhibitor of mutant K-Ras G12C.

KRASG12C IN-14 (compound 15), a potent inhibitor specifically designed for the KRAS G12C mutation, exhibits impressive efficacy in impeding CYPA-dependent KRAS-BRAF interaction and ERK phosphorylation in NCI-H358 cells, both with an IC 50 of 0.002 μM.

KRASG12C IN-17 is an orally active covalent inhibitor of KRASG12C, demonstrating potent inhibitory activity in KRASG12C-mutant cancer cells (NCI-H23 IC50 = 0.7 nM; NCI-H358 IC50 = 0.5 nM). It efficiently and irreversibly forms a covalent bond with KRASG12C in both GDP-bound and GMPPNP-bound states, with a modification rate exceeding 96%. KRASG12C IN-17 is applicable for research on KRAS-driven tumors, including colorectal cancer.

KRASG12C IN-18 is an orally active covalent inhibitor of KRASG12C, achieving complete covalent binding to KRASG12C in both GDP- and GMPPNP-bound states. It exhibits significant antiproliferative activity against KRASG12C and its resistant mutations (including KRASG12C/R68S) with an IC50 in the low nanomolar range. KRASG12C IN-18 demonstrates notable in vivo efficacy in KRASG12C-driven solid tumors and KRASG12C/R68S xenograft models, making it applicable for colorectal adenocarcinoma research.

KRASG12C IN-19 is a selective inhibitor of KRASG12C. It exhibits potent antiproliferative activity against the KRASG12C-mutant non-small cell lung cancer (NSCLC) cell line H358, with an IC50 of 7.6 nM, and effectively inhibits downstream ERK phosphorylation (IC50= 24.06 nM). It shows no significant inhibitory activity on KRASG12V and KRASG12D mutant cancer cells (PANC 1, Panc 03.27, AsPC 1, and GP2d cells) with IC50 values greater than 10,000 nM. KRASG12C IN-19 rapidly forms a covalent bond with KRASG12V-GDP, leading to dose-dependent inhibition of the downstream KRAS pathway. This compound is suitable for research on KRASG12C-driven cancers, including non-small cell lung cancer, pancreatic cancer, and colorectal cancer.