Approach for targeting Ras with small molecules that activate SOS-mediated nucleotide exchange.

Burns MC, Sun Q, Daniels RN, Camper D, Kennedy JP, Phan J, Olejniczak ET, Lee T, Waterson AG, Rossanese OW, Fesik SW
Proc Natl Acad Sci U S A. 2014 111 (9): 3401-6

PMID: 24550516 · PMCID: PMC3948241 · DOI:10.1073/pnas.1315798111

Aberrant activation of the small GTPase Ras by oncogenic mutation or constitutively active upstream receptor tyrosine kinases results in the deregulation of cellular signals governing growth and survival in ∼30% of all human cancers. However, the discovery of potent inhibitors of Ras has been difficult to achieve. Here, we report the identification of small molecules that bind to a unique pocket on the Ras:Son of Sevenless (SOS):Ras complex, increase the rate of SOS-catalyzed nucleotide exchange in vitro, and modulate Ras signaling pathways in cells. X-ray crystallography of Ras:SOS:Ras in complex with these molecules reveals that the compounds bind in a hydrophobic pocket in the CDC25 domain of SOS adjacent to the Switch II region of Ras. The structure-activity relationships exhibited by these compounds can be rationalized on the basis of multiple X-ray cocrystal structures. Mutational analyses confirmed the functional relevance of this binding site and showed it to be essential for compound activity. These molecules increase Ras-GTP levels and disrupt MAPK and PI3K signaling in cells at low micromolar concentrations. These small molecules represent tools to study the acute activation of Ras and highlight a pocket on SOS that may be exploited to modulate Ras signaling.

MeSH Terms (17)

Chromatography, Liquid Chromatography, Thin Layer Crystallography, X-Ray Fluorescence Polarization HeLa Cells Humans Indoles Ligands Magnetic Resonance Spectroscopy Mass Spectrometry Models, Molecular Molecular Structure Multiprotein Complexes Piperidines Protein Conformation Proto-Oncogene Proteins p21(ras) SOS1 Protein

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