MRTX1133--Anti-tumor efficacy of a potent and selective non-covalent KRASG12D inhibitor

MRTX-1133 is one of the first potent, selective KRAS G12D inhibitors that binds noncovalently to the S-IIP of the active and inactive states of KRAS G12D [33]. Preclinical studies showed significant efficacy, with tumor regression in xenograft mouse models occurring in a dose-dependent manner [34]. These promising preclinical data led to the ongoing phase I/II study of MRTX1133 in KRAS G12D-mutant solid tumors [NCT05737706].

Recent progress in targeting KRASG12C has provided both insight and inspiration for targeting alternative KRAS mutants. In this study, we evaluated the mechanism of action and anti-tumor efficacy of MRTX1133, a potent, selective and non-covalent KRASG12D inhibitor. MRTX1133 demonstrated a high-affinity interaction with GDP-loaded KRASG12D with KD and IC50 values of ~0.2 pM and <2 nM, respectively, and ~700-fold selectivity for binding to KRASG12D as compared to KRASWT. MRTX1133 also demonstrated potent inhibition of activated KRASG12D based on biochemical and co-crystal structural analyses. MRTX1133 inhibited ERK1/2 phosphorylation and cell viability in KRASG12D-mutant cell lines, with median IC50 values of ~5 nM, and demonstrated >1,000-fold selectivity compared to KRASWT cell lines. MRTX1133 exhibited dose-dependent inhibition of KRAS-mediated signal transduction and marked tumor regression (≥30%) in a subset of KRASG12D-mutant cell-line-derived and patient-derived xenograft models, including eight of 11 (73%) pancreatic ductal adenocarcinoma (PDAC) models. Pharmacological and CRISPR-based screens demonstrated that co-targeting KRASG12D with putative feedback or bypass pathways, including EGFR or PI3Kα, led to enhanced anti-tumor activity. Together, these data indicate the feasibility of selectively targeting KRAS mutants with non-covalent, high-affinity small molecules and illustrate the therapeutic susceptibility and broad dependence of KRASG12D mutation-positive tumors on mutant KRAS for tumor cell growth and survival.

In vitro, MRTX1133 significantly inhibits KRASG12D signaling in cancer cell lines. In PANC-1 cells, a pancreatic ductal adenocarcinoma (PDAC) cell line, MRTX1133 reduced cell proliferation with an IC50 of approximately 1 nmol/L. Treatment lasted 24 to 72 hours, consistently showing potent inhibition of MAPK and ERK signaling. A colorectal cancer cell line with the KRASG12D mutation, MRTX1133 (10 nmol/L) was applied for 48 hours. Western blot analysis showed a significant decrease in phosphorylated ERK (pERK) levels, confirming KRASG12D signaling inhibition. In vivo, MRTX1133 treatment (30 mg/kg i.p. bid) inhibited 80% pancreatic tumor growth in 21 days, while oral dosing (50 mg/kg qd) reduced colorectal tumors by 70% in 28 days, both specifically targeting KRASG12D mutants without major toxicity in xenograft models. In conclusion, MRTX1133 has shown promising preclinical results in inhibiting KRASG12D-driven tumor growth. Its high selectivity and potent anti-tumor efficacy make it a strong candidate for further clinical development. Future studies will be essential to determine its therapeutic potential in human cancer patients harboring KRASG12D mutations.