biostudies-literatureHodges TRCancer Research UKNCRR NIH HHSNIH Office of the DirectorNational Cancer InstituteLustgarten FoundationNCI NIH HHSNIH HHS8875-8894https://www.ebi.ac.uk/biostudies/studies/S-EPMC8314423biostudies-literatureUnknown61(19)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.Journal of medicinal chemistryDiscovery and Structure-Based Optimization of Benzimidazole-Derived Activators of SOS1-Mediated Nucleotide Exchange on RAS.PMC8314423DP1 CA174419S10 RR025677P30 CA0684855 P50 CA095103DP1 OD0069331156622897Howes JEStadtmueller HLittle AJBurns MCSarkar DPhan JScharn DMcConnell DBAbbott JRAkan DTBrowning CSalovich JMRossanese OWWaterson AGFesik SWSun QCoker JASai JBeesetty YSobolik TArnold ALHodges TRfalseDiscovery and Structure-Based Optimization of Benzimidazole-Derived Activators of SOS1-Mediated Nucleotide Exchange on RAS.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.2018-01-01T00:00:00Z2018 Oct2024-10-16T12:44:02.133Z2022-02-11T00:13:46.625ZS-EPMC83144233020500510.1021/acs.jmedchem.8b01108