guanosine-diphosphate and benzimidazole

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; hence, SOS1 is an attractive therapeutic target for its role in modulating RAS activation. Here, we describe a new series of benzimidazole-derived SOS1 agonists. Using structure-guided design, we discovered small molecules that increase nucleotide exchange on RAS in vitro at submicromolar concentrations, bind to SOS1 with low double-digit nanomolar affinity, rapidly enhance cellular RAS-GTP levels, and invoke biphasic signaling changes in phosphorylation of ERK 1/2. These compounds represent the most potent series of SOS1 agonists reported to date.

Topics: Benzimidazoles; Drug Discovery; Extracellular Signal-Regulated MAP Kinases; Guanine Nucleotide Exchange Factors; Guanosine Diphosphate; Guanosine Triphosphate; HeLa Cells; Humans; Phosphorylation; Protein Conformation; Proto-Oncogene Proteins p21(ras); SOS1 Protein; Structure-Activity Relationship