• Till Maurer, Lindsay S Garrenton, Angela Oh, Keith Pitts, Daniel J Anderson, Nicholas J Skelton, Benjamin P Fauber, Borlan Pan, Shiva Malek, David Stokoe, Mary J C Ludlam, Krista K Bowman, Jiansheng Wu, Anthony M Giannetti, Melissa A Starovasnik, Ira Mellman, Peter K Jackson, Joachim Rudolph, Weiru Wang, and Guowei Fang.
• Structural Biology, Genentech, Inc., One DNA Way, South San Francisco, CA 94080, USA.
• Proc. Natl. Acad. Sci. U.S.A. 2012 Apr 3; 109 (14): 5299-304.

AbstractThe Ras gene is frequently mutated in cancer, and mutant Ras drives tumorigenesis. Although Ras is a central oncogene, small molecules that bind to Ras in a well-defined manner and exert inhibitory effects have not been uncovered to date. Through an NMR-based fragment screen, we identified a group of small molecules that all bind to a common site on Ras. High-resolution cocrystal structures delineated a unique ligand-binding pocket on the Ras protein that is adjacent to the switch I/II regions and can be expanded upon compound binding. Structure analysis predicts that compound-binding interferes with the Ras/SOS interactions. Indeed, selected compounds inhibit SOS-mediated nucleotide exchange and prevent Ras activation by blocking the formation of intermediates of the exchange reaction. The discovery of a small-molecule binding pocket on Ras with functional significance provides a new direction in the search of therapeutically effective inhibitors of the Ras oncoprotein.

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