Son of sevenless homologue 1 (SOS1) is a guanine nucleotide exchange factor that catalyzes the exchange of GDP for GTP on RAS. In its active form, GTP-bound RAS is responsible for numerous critical cellular processes. Aberrant RAS activity is involved in ~30% of all human cancers. Given its role in modulating RAS activation, SOS1 is thus an attractive therapeutic target. Using both NMR-based fragment screening and high-throughput biochemical screening, we have discovered multiple series of small molecules that bind to a novel site on SOS1 and increase nucleotide exchange on RAS in vitro. Using structure-guided design, these compounds were optimized for binding to SOS1, achieving single digit nanomolar affinity. Optimized compounds potently agonize SOS1 function and display robust effects on downstream RAS signaling, including rapid enhancement of cellular RAS-GTP levels and induction of biphasic signaling changes in phosphorylation of extracellular regulated kinase1/2 (ERK 1/2).

Discovery of benzimidazole activators of SOS1-mediated nucleotide exchange on RAS

ACS Spring Meeting 2021

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