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.