KRASG12D-IN-7 is a selective inhibitor of KRASG12D. It exhibits strong binding affinity to KRASG12D in both GDP-bound and GTP-bound states, with Kd values of 1.12 nM and 1.86 nM, respectively. This compound inhibits the proliferation of KRASG12D-bearing AsPC-1 cells with an IC50 of 10 nM and disrupts MAPK signaling. In AsPC-1 cells, KRASG12D-IN-7 induces G0/G1 phase arrest and apoptosis (apoptosis), and significantly suppresses colony formation. The inhibitor is applicable for research on cancers with KRASG12D mutations, particularly pancreatic ductal adenocarcinoma (PDAC).

KRas (G12D):1.12 nM (Kd)

KRASG12D-IN-7 (Compound (R)-5a) demonstrates potent and selective antiproliferative activity against AsPC-1 cells with a KRASG12D mutation (IC50 = 10 nM), GP2D cells (IC50 = 2.7 nM), AGS cells (IC50 = 6.1 nM), HPAF-II cells (IC50 = 6.8 nM), and Ls513 cells (IC50 = 27.3 nM), while showing negligible inhibition on other KRAS mutants (H358 G12C, G12S) and KRAS wild-type cell lines (IC50 > 1000 nM). The compound binds to both GDP- and GTP-bound forms of KRAS G12D, selectively blocking the interaction of GDP-bound KRAS G12D with SOS1, and disrupting the linkage between GTP-bound KRAS G12D and RAF1. Additionally, KRASG12D-IN-7 (1-1000 nM, 3 hours) leads to a dose-dependent reduction of p-ERK and p-S6 protein levels in AsPC-1 cells, effectively inhibiting the downstream MAPK signaling pathway in KRAS-mutant cells. Furthermore, KRASG12D-IN-7 (1-1000 nM, 24-72 hours) induces G0/G1 phase arrest and apoptosis in AsPC-1 cells, and a concentration of 5 nM over 10 days significantly suppresses colony formation in these cells.