Discovery of Sulfonamide-Derived Agonists of SOS1-Mediated Nucleotide Exchange on RAS Using Fragment-Based Methods

The nucleotide exchange
factor Son of Sevenless (SOS) catalyzes
the activation of RAS by converting it from its inactive GDP-bound
state to its active GTP-bound state. Recently, we have reported the
discovery of small-molecule allosteric activators of SOS1 that can
increase the amount of RAS-GTP in cells. The compounds can inhibit
ERK phosphorylation at higher concentrations by engaging a feedback
mechanism. To further study this process, we sought different chemical
matter from an NMR-based fragment screen using selective methyl labeling.
To aid this process, several Ile methyl groups located in different
binding sites of the protein were assigned and used to categorize
the NMR hits into different classes. Hit to lead optimization using
an iterative structure-based design paradigm resulted in compounds
with improvements in binding affinity. These improved molecules of
a different chemical class increase SOS1cat-mediated nucleotide
exchange on RAS and display cellular action consistent with our prior
results.