PDBsum entry 6d56

Signaling protein

PDB id: 6d56

Contents

Protein chains

166 a.a.

469 a.a.

Ligands

GNP

FVM

FMT ×6

GOL ×2

Metals

_MG

_NA

Waters ×1144

References listed in PDB file

Key reference

• Title: Discovery and structure-Based optimization of benzimidazole-Derived activators of sos1-Mediated nucleotide exchange on ras.
• Authors: T.R.Hodges, J.R.Abbott, A.J.Little, D.Sarkar, J.M.Salovich, J.E.Howes, D.T.Akan, J.Sai, A.L.Arnold, C.Browning, M.C.Burns, T.Sobolik, Q.Sun, Y.Beesetty, J.A.Coker, D.Scharn, H.Stadtmueller, O.W.Rossanese, J.Phan, A.G.Waterson, D.B.Mcconnell, S.W.Fesik.
• Ref.: J Med Chem, 2018, 61, 8875-8894. [DOI no: 10.1021/acs.jmedchem.8b01108]
• PubMed id: 30205005

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.

Secondary reference #1

• Title: Approach for targeting ras with small molecules that activate sos-Mediated nucleotide exchange.
• Authors: M.C.Burns, Q.Sun, R.N.Daniels, D.Camper, J.P.Kennedy, J.Phan, E.T.Olejniczak, T.Lee, A.G.Waterson, O.W.Rossanese, S.W.Fesik.
• Ref.: Proc Natl Acad Sci U S A, 2014, 111, 3401-3406. [DOI no: 10.1073/pnas.1315798111]
• PubMed id: 24550516