News | TargetMol

2024/12/15

WIKIMOLE — MRTX1133

MRTX1133，T9303, is a potent, selective and non-covalent inhibitor of KRAS^G12D. It exhibits nanomolar binding affinity in cell experiments (KD of 0.2 pM for KRAS^G12D) and demonstrates significant in vivo efficacy in tumor models driven by KRAS^G12D mutations.

Mechanism of Action

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.

Biological Applications

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.