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
  • 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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