Discovery of Five SOS2 Fragment Hits with Binding Modes Determined by SOS2 X‑Ray Cocrystallography

SOS1 and SOS2 are
guanine nucleotide exchange factors that mediate
RTK-stimulated RAS activation. Selective SOS1:KRAS PPI inhibitors
are currently under clinical investigation, whereas there are no reports
to date of SOS2:KRAS PPI inhibitors. SOS2 activity is implicated in
MAPK rebound when divergent SOS1 mutant cell lines are treated with
the SOS1 inhibitor BI-3406; therefore, SOS2:KRAS inhibitors are of
therapeutic interest. In this report, we detail a fragment-based screening
strategy to identify X-ray cocrystal structures of five diverse fragment
hits bound to SOS2.