Design and Discovery of MRTX0902, a Potent, Selective, Brain-Penetrant, and Orally Bioavailable Inhibitor of the SOS1:KRAS Protein-Protein Interaction.

doi:10.1021/acs.jmedchem.2c00741

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Article

Design and Discovery of MRTX0902, a Potent, Selective, Brain-Penetrant, and Orally Bioavailable Inhibitor of the SOS1:KRAS Protein-Protein Interaction.

Journal of medicinal chemistry - 28 Jul 2022

Ketcham John M, Haling Jacob, Khare Shilpi, Bowcut Vickie, Briere David M, Burns Aaron C, Gunn Robin J, Ivetac Anthony, Kuehler Jon, Kulyk Svitlana, Laguer Jade, Lawson J David, Moya Krystal, Nguyen Natalie, Rahbaek Lisa, Saechao Barbara, Smith Christopher R, Sudhakar Niranjan, Thomas Nicole C, Vegar Laura, Vanderpool Darin, Wang Xiaolun, Yan Larry, Olson Peter, Christensen James G, Marx Matthew A

Abstract excerpt

SOS1 is one of the major guanine nucleotide exchange factors that regulates the ability of KRAS to cycle through its "on" and "off" states. Disrupting the SOS1:KRASG12C protein-protein interaction (PPI) can increase the proportion of GDP-loaded KRASG12C, providing a strong mechanistic rationale for combining inhibitors of the SOS1:KRAS complex with inhibitors like MRTX849 that target GDP-loaded KRASG12C. In this...

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PMID: 35833726
DOI: 10.1021/acs.jmedchem.2c00741
PMCID: PMC9340770

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