2. Academic Validation
  3. Discovery and Structure-Based Optimization of Benzimidazole-Derived Activators of SOS1-Mediated Nucleotide Exchange on RAS

Discovery and Structure-Based Optimization of Benzimidazole-Derived Activators of SOS1-Mediated Nucleotide Exchange on RAS

  • J Med Chem. 2018 Oct 11;61(19):8875-8894. doi: 10.1021/acs.jmedchem.8b01108.
Timothy R Hodges,  Jason R Abbott,  Andrew J Little,  Dhruba Sarkar,  James M Salovich,  Jennifer E Howes,  Denis T Akan,  Jiqing Sai,  Allison L Arnold,  Carrie Browning,  Michael C Burns,  Tammy Sobolik,  Qi Sun,  Yugandhar Beesetty,  Jesse A Coker,  Dirk Scharn 1,  Heinz Stadtmueller 1,  Olivia W Rossanese,  Jason Phan,  Alex G Waterson 2,  Darryl B McConnell 1,  Stephen W Fesik 2
Affiliations

Affiliations

  • 1 Boehringer Ingelheim RCV GmbH & Co. KG , Doktor-Boehringer-Gasse 5-11 , 1120 Vienna , Austria.
  • 2 Department of Chemistry , Vanderbilt University , Nashville , Tennessee 37232-0146 , United States.
PMID: 30205005 DOI: 10.1021/acs.jmedchem.8b01108
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.

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