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

Publication Type:

Journal Article

Authors:

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

Source:

J Med Chem, Volume 65, Issue 14, p.9678-9690 (2022)

Keywords:

Acetonitriles, Animals, Brain, Cell Line, Tumor, Humans, Mice, Mutation, Piperazines, Proto-Oncogene Proteins p21(ras), Pyrimidines, SOS1 Protein

Abstract:

<p>SOS1 is one of the major guanine nucleotide exchange factors that regulates the ability of KRAS to cycle through its &quot;on&quot; and &quot;off&quot; states. Disrupting the SOS1:KRAS protein-protein interaction (PPI) can increase the proportion of GDP-loaded KRAS, providing a strong mechanistic rationale for combining inhibitors of the SOS1:KRAS complex with inhibitors like MRTX849 that target GDP-loaded KRAS. In this report, we detail the design and discovery of MRTX0902─a potent, selective, brain-penetrant, and orally bioavailable SOS1 binder that disrupts the SOS1:KRAS PPI. Oral administration of MRTX0902 in combination with MRTX849 results in a significant increase in antitumor activity relative to that of either single agent, including tumor regressions in a subset of animals in the MIA PaCa-2 tumor mouse xenograft model.</p>

PDB: 
7UKS, 7UKR
Detector: 
EIGER
Beamline: 
24-ID-E