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Identification of MRTX1133, a Noncovalent, Potent, and Selective KRAS G12D Inhibitor

2021; American Chemical Society; Volume: 65; Issue: 4 Linguagem: Inglês

10.1021/acs.jmedchem.1c01688

1520-4804

Xiaolun Wang, Shelley Allen, James F. Blake, Vickie Bowcut, David M. Briere, Andrew Calinisan, Joshua R. Dahlke, Jay B. Fell, John P. Fischer, Robin J. Gunn, Jill Hallin, Jade Laguer, J. David Lawson, James Medwid, Brad Newhouse, Phong Nguyen, Jacob M. O’Leary, Peter Olson, Spencer Pajk, Lisa Rahbæk, Mareli Rodriguez, Christopher R. Smith, Tony P. Tang, Nicole C. Thomas, Darin Vanderpool, Guy Vigers, James G. Christensen, Matthew A. Marx,

Melanoma and MAPK Pathways

KRASG12D, the most common oncogenic KRAS mutation, is a promising target for the treatment of solid tumors. However, when compared to KRASG12C, selective inhibition of KRASG12D presents a significant challenge due to the requirement of inhibitors to bind KRASG12D with high enough affinity to obviate the need for covalent interactions with the mutant KRAS protein. Here, we report the discovery and characterization of the first noncovalent, potent, and selective KRASG12D inhibitor, MRTX1133, which was discovered through an extensive structure-based activity improvement and shown to be efficacious in a KRASG12D mutant xenograft mouse tumor model.