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Fesik Lab

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

AUTHORS

Burns MCMichael C , Sun QQi , Daniels RNR Nathan , Camper DDeMarco , Kennedy JPJ Phillip , Phan JJason , Olejniczak ETEdward T , Lee TTaekyu , Waterson AGAlex G , Rossanese OWOlivia W , Fesik SWStephen W . Proceedings of the National Academy of Sciences of the United States of America. 2014 3 4; 111(9). 3401-6

ABSTRACT

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.