| Literature DB >> 34889605 |
Xiaolun Wang1, Shelley Allen2, James F Blake2, Vickie Bowcut1, David M Briere1, Andrew Calinisan1, Joshua R Dahlke2, Jay B Fell2, John P Fischer2, Robin J Gunn1, Jill Hallin1, Jade Laguer1, J David Lawson1, James Medwid1, Brad Newhouse2, Phong Nguyen2, Jacob M O'Leary2, Peter Olson1, Spencer Pajk2, Lisa Rahbaek1, Mareli Rodriguez2, Christopher R Smith1, Tony P Tang2, Nicole C Thomas1, Darin Vanderpool1, Guy P Vigers2, James G Christensen1, Matthew A Marx1.
Abstract
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.Entities:
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Year: 2021 PMID： 34889605 DOI： 10.1021/acs.jmedchem.1c01688
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446