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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Benzimidazoles / chemistry
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Benzimidazoles / pharmacology*
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Drug Discovery / standards*
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Guanine Nucleotide Exchange Factors / chemistry
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Guanine Nucleotide Exchange Factors / metabolism*
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Guanosine Diphosphate / metabolism
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Guanosine Triphosphate / metabolism
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HeLa Cells
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Humans
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Phosphorylation
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Protein Conformation
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Proto-Oncogene Proteins p21(ras) / chemistry
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Proto-Oncogene Proteins p21(ras) / metabolism*
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SOS1 Protein / agonists*
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SOS1 Protein / metabolism*
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Structure-Activity Relationship
Substances
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Benzimidazoles
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Guanine Nucleotide Exchange Factors
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SOS1 Protein
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SOS1 protein, human
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Guanosine Diphosphate
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Guanosine Triphosphate
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benzimidazole
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Extracellular Signal-Regulated MAP Kinases
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Proto-Oncogene Proteins p21(ras)