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- W2890164144 abstract "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." @default.
- W2890164144 created "2018-09-27" @default.
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- W2890164144 date "2018-09-11" @default.
- W2890164144 modified "2023-10-14" @default.
- W2890164144 title "Discovery and Structure-Based Optimization of Benzimidazole-Derived Activators of SOS1-Mediated Nucleotide Exchange on RAS" @default.
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- W2890164144 doi "https://doi.org/10.1021/acs.jmedchem.8b01108" @default.
- W2890164144 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/8314423" @default.
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- W2890164144 hasPublicationYear "2018" @default.
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