Niranjan Sudhakar, Larry Yan, Fadia Qiryaqos, Lars D Engstrom, Jade Laguer, Andrew Calinisan, Allan Hebbert, Laura Waters, Krystal Moya, Vickie Bowcut, Laura Vegar, John M Ketcham, Anthony Ivetac, Christopher R Smith, J David Lawson, Lisa Rahbaek, Jeffrey Clarine, Natalie Nguyen, Barbara Saechao, Cody Parker, Adam J Elliott, Darin Vanderpool, Leo He, Laura D Hover, Julio Fernandez-Banet, Silvia Coma, Jonathan A Pachter, Jill Hallin, Matthew A Marx, David M Briere, James G Christensen, Peter Olson, Jacob Haling, Shilpi Khare
KRAS is the most frequently mutated oncogene in human cancer and facilitates uncontrolled growth through hyperactivation of the RTK/MAPK pathway. The Son of Sevenless homolog 1 (SOS1) protein functions as a guanine nucleotide exchange factor (GEF) for the RAS subfamily of small GTPases and represents a druggable target in the pathway. Using a structure-based drug discovery approach, MRTX0902 was identified as a selective and potent SOS1 inhibitor that disrupts the KRAS:SOS1 protein-protein interaction to prevent SOS1-mediated nucleotide exchange on KRAS and translates into an anti-proliferative effect in cancer cell lines with genetic alterations of the KRAS-MAPK pathway...
April 19, 2024: Molecular Cancer Therapeutics