A small-molecule mimic of a peptide docking motif inhibits the protein kinase PDK1.

ABSTRACT: There is great interest in developing selective protein kinase inhibitors by targeting allosteric sites, but these sites often involve protein-protein or protein-peptide interfaces that are very challenging to target with small molecules. Here we present a systematic approach to targeting a functionally conserved allosteric site on the protein kinase PDK1 called the PDK1-interacting fragment (PIF)tide-binding site, or PIF pocket. More than two dozen prosurvival and progrowth kinases dock a conserved peptide tail into this binding site, which recruits them to PDK1 to become activated. Using a site-directed chemical screen, we identified and chemically optimized ligand-efficient, selective, and cell-penetrant small molecules (molecular weight ∼ 380 Da) that compete with the peptide docking m

SUBMITTER: Rettenmaier TJ 

PROVIDER: S-EPMC4284534 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature