Article ｜ 22 Dec 2023

WIKIMOLE — MRTX1133

By TargetMol

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.

 

 

 

Reference

[1] Hallin J, Bowcut V, Calinisan A, et al. Anti-tumor efficacy of a potent and selective non-covalent KRASG12D inhibitor. Nat Med. 2022;28(10):2171-2182. doi:10.1038/s41591-022-02007-7

[2] Wang X, Allen S, Blake JF, et al. Identification of MRTX1133, a Noncovalent, Potent, and Selective KRASG12D Inhibitor. J Med Chem. 2022;65(4):3123-3133. doi:10.1021/acs.jmedchem.1c01688

[3] Wei D, Wang L, Zuo X, Maitra A, Bresalier RS. A small molecule with big impact: MRTX1133 targets the KRASG12D mutation in pancreatic cancer. Clin Cancer Res. Published online October 13, 2023. doi:10.1158/1078-0432.CCR-23-2098

[4] Buscail L. Pancreatic cancer: Exosomes for targeting KRAS in the treatment of pancreatic cancer. Nat Rev Gastroenterol Hepatol. 2017;14(11):636-638. doi:10.1038/nrgastro.2017.113