Highly specific, bisubstrate-competitive Src inhibitors from DNA-templated macrocycles.

ABSTRACT: Protein kinases are attractive therapeutic targets, but their high sequence and structural conservation complicates the development of specific inhibitors. We recently identified, in a DNA-templated macrocycle library, inhibitors with unusually high selectivity among Src-family kinases. Starting from these compounds, we developed and characterized in molecular detail potent macrocyclic inhibitors of Src kinase and its cancer-associated 'gatekeeper' mutant. We solved two cocrystal structures of macrocycles bound to Src kinase. These structures reveal the molecular basis of the combined ATP- and substrate peptide-competitive inhibitory mechanism and the remarkable kinase specificity of the compounds. The most potent compounds inhibit Src activity in cultured mammalian cells. Our work establi

SUBMITTER: Georghiou G 

PROVIDER: S-EPMC3307835 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature