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

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.

Automated summary

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.