MRTX1133

MRTX1133 is a potent, selective, noncovalent KRASG12D inhibitor. It has picomolar binding affinity, single-digit nanomolar activity in cellular assays. In addition, it has significant in vivo efficacy in tumor models harboring KRASG12D mutations.

KRAS G12D is the most common KRAS mutation in human tumors, frequently found in pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC), and non-small cell lung cancer (NSCLC). Studies indicate that MRTX1133 exhibits significant anti-tumor effects in cell lines HPAC (pancreatic cancer) and GP2D (colorectal cancer) with KRAS G12D mutation, and it demonstrates no apparent cytotoxicity. Currently, a Phase I/II clinical trial (NCT05737706) has been initiated, targeting patients with advanced solid tumors (PDAC, NSCLC, colorectal cancer, etc.) with KRAS KRAS G12D mutation. As an exceptionally potent, selective and non-covalent inhibitor of KRAS G12D, the combination of MRTX1133 and its derivatives with inhibitors targeting signaling pathways such as EGFR, MAPK, and PI3K/AKT holds promise as a next-generation therapeutic strategy for cancers like PDAC, CRC, and NSCLC.

2621928-55-8

MRTX1133 is a potent, selective, and noncovalent inhibitor of KRAS G12D. MRTX1133 exhibits an estimated KD against KRAS G12D of 0.2 pM. MRTX1133 inhibits mutant KRAS-dependent signal transduction by preventing SOS1-catalyzed nucleotide exchange and/or formation of the KRAS G12D/GTP/RAF1 complex. MRTX1133 selectively inhibits KRAS G12D mutant tumor cells with no effect on KRAS wild-type. MRTX1133 exhibits single digit nanomolar activity in cellular assays and marked in vivo efficacy in tumor models harboring KRAS G12D mutations.

C33H31F3N6O2

MRTX1133 binds to KRAS G12D, inhibiting nucleotide exchange catalyzed by SOS1 and preventing the formation of the KRAS G12D complex with downstream effector RAF1. This action disrupts the signaling cascade dependent on mutant KRAS in cancer cells selectively. In xenograft mouse models, MRTX1133 significantly reduces tumor growth in a dose-dependent manner and decreases phosphorylation of the downstream signaling molecule ERK.

600.63

MAPK; GPCR/G Protein

0.9802

HPAC (Human Pancreatic Cancer); PDAC (Pancreatic ductal adenocarcinoma); NSCLC (Non-small-cell lung cancer); CRC (Colorectal Cancer)

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Ras