4.7 Article

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

Journal

JOURNAL OF MEDICINAL CHEMISTRY
Volume -, Issue -, Pages -

Publisher

AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.2c00741

Keywords

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Funding

  1. National Institute of General Medical Sciences from the U.S. National Institutes of Health [P30 GM124165]
  2. NIH-ORIP HEI grant [S10OD021527]
  3. Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility [DE-AC02-06CH11357]
  4. Mirati Therapeutics

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SOS1 is an important regulator of KRAS, and disrupting the SOS1:KRASG12C protein-protein interaction can increase the proportion of GDP-loaded KRASG12C. In this study, researchers designed and discovered MRTX0902, a potent and selective SOS1 binder that can disrupt the SOS1:KRASG12C interaction. Combining oral administration of MRTX0902 with MRTX849 has shown significant antitumor activity, including tumor regressions in a subset of animals in the MIA PaCa-2 tumor mouse xenograft model.
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 report, we detail the design and discovery of MRTX0902-a potent, selective, brain-penetrant, and orally bioavailable SOS1 binder that disrupts the SOS1:KRASG12C 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.

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