Small-molecule ligands bind to a distinct pocket in Ras and inhibit SOS-mediated nucleotide exchange activity

  • Proc Natl Acad Sci U S A. 2012 Apr 3;109(14):5299-304. doi: 10.1073/pnas.1116510109.
Till Maurer  1 ,  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 ,  Guowei Fang
Affiliations
  • 1. Structural Biology, Genentech, Inc., One DNA Way, South San Francisco, CA 94080, USA.
PMID: 22431598 DOI: 10.1073/pnas.1116510109
Abstract

The 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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