6CUR

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

Summary for 6CUR

• Entry DOI: 10.2210/pdb6cur/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: 95845.94

Authors

Phan, J.,Abbott, J.,Fesik, S.W. (deposition date: 2018-03-26, release date: 2019-02-06, Last modification date: 2024-10-30)

Primary citation

Abbott, J.R.,Patel, P.A.,Howes, J.E.,Akan, D.T.,Kennedy, J.P.,Burns, M.C.,Browning, C.F.,Sun, Q.,Rossanese, O.W.,Phan, J.,Waterson, A.G.,Fesik, S.W.
Discovery of Quinazolines That Activate SOS1-Mediated Nucleotide Exchange on RAS.
ACS Med Chem Lett, 9:941-946, 2018

PubMed Abstract: Proteins in the RAS family are important regulators of cellular signaling and, when mutated, can drive cancer pathogenesis. Despite considerable effort over the last 30 years, RAS proteins have proven to be recalcitrant therapeutic targets. One approach for modulating RAS signaling is to target proteins that interact with RAS, such as the guanine nucleotide exchange factor (GEF) son of sevenless homologue 1 (SOS1). Here, we report hit-to-lead studies on quinazoline-containing compounds that bind to SOS1 and activate nucleotide exchange on RAS. Using structure-based design, we refined the substituents attached to the quinazoline nucleus and built in additional interactions not present in the initial HTS hit. Optimized compounds activate nucleotide exchange at single-digit micromolar concentrations in vitro. In HeLa cells, these quinazolines increase the levels of RAS-GTP and cause signaling changes in the mitogen-activated protein kinase/extracellular regulated kinase (MAPK/ERK) pathway.

PubMed: 30258545
DOI: 10.1021/acsmedchemlett.8b00296

Experimental method

X-RAY DIFFRACTION (1.73 Å)