Mutant KRAS is an attractive drug target for the treatment of a number of cancers for many decades. Until recently, the high affinity of KRAS for GDP/GTP and the lack of any other apparent binding pocket have significantly hampered the development of KRAS inhibitors. KRAS inhibitor relies on a reactive warhead forming a stable covalent bond with the mutant Cys12. KRAS^G12D is the most common mutation (33%) among KRAS mutant tumors. It lacks a reactive residue adjacent to the switch II pocket as evidenced in recent attempts. Therefore, there requires a novel approach toward the identification of selective inhibitors. In this study, MRTX1133 is a potent, selective, noncovalent KRAS^G12D 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 KRAS^G12D mutations.

MRTX1133 is a noncovalent, potent, and selective KRAS ^G12D inhibitor.

MRTX1133 is an exceptionally potent and selective KRAS^G12D inhibitor. It optimally fills the switch II pocket and extends three substituents to favorably interact with the protein. The K_D is 0.2 pM. MRTX1133 inhibits ERK phosphorylation in the AGS cell line with an IC₅₀ of 2 nM. In a 2D viability assay, the IC₅₀ of MRTX1133 is 6 nM against the same cell line. It shows more than 500-fold selectivity against MKN1, a cell line that is dependent on KRAS for its growth and survival due to the amplification of wild-type KRAS.  In addition, MRTX1133 (3-30 mg/kg) shows dose-dependent antitumor activity. However, there is no significant antitumor activity in the non-KRAS^G12D tumor model MKN1.

In summary, MRTX1133 is a highly selective, first-in-class inhibitor of KRAS G12D. MRTX1133 targets the KRAS G12D protein in both active and inactive states. MRTX1133 selectively inhibits KRAS G12D mutant, but not KRAS wild-type, tumor cells.