Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 61, Issue 19, Pages 8875-8894Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.8b01108
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Funding
- U.S. National Institutes of Health, NIH Director's Pioneer Award [DP1OD006933/DP1CA174419]
- Lustgarten Foundation Research Investigator Grant
- National Cancer Institute SPORE Grant in GI Cancer [5P50A095103-09]
- Vanderbilt Institute of Chemical Biology
- Vanderbilt Ingram Cancer Center [P30 CA68485]
- NIH SIG grant [I1S-10RR025677-01]
- Vanderbilt University
- U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-06CH11357]
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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 similar to 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.
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