6D56

Ras:SOS:Ras in complex with a small molecule activator

Summary for 6D56

• Entry DOI: 10.2210/pdb6d56/pdb
• Descriptor: GTPase HRas, Son of sevenless homolog 1, PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER, ... (10 entities in total)
• Functional Keywords: ras, sos, inhibitor, oncoprotein, protein-protein complex, mapk, signaling protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 3
• Total formula weight: 95886.99

Authors

Phan, J.,Hodges, T.,Fesik, S.W. (deposition date: 2018-04-19, release date: 2018-09-19, Last modification date: 2024-10-30)

Primary citation

Hodges, T.R.,Abbott, J.R.,Little, A.J.,Sarkar, D.,Salovich, J.M.,Howes, J.E.,Akan, D.T.,Sai, J.,Arnold, A.L.,Browning, C.,Burns, M.C.,Sobolik, T.,Sun, Q.,Beesetty, Y.,Coker, J.A.,Scharn, D.,Stadtmueller, H.,Rossanese, O.W.,Phan, J.,Waterson, A.G.,McConnell, D.B.,Fesik, S.W.
Discovery and Structure-Based Optimization of Benzimidazole-Derived Activators of SOS1-Mediated Nucleotide Exchange on RAS.
J. Med. Chem., 61:8875-8894, 2018

PubMed 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.

PubMed: 30205005
DOI: 10.1021/acs.jmedchem.8b01108

Experimental method

X-RAY DIFFRACTION (1.68 Å)