%0 Journal Article
%T Fragment-based Discovery of a Small-Molecule Protein Kinase C-iota Inhibitor Binding Post-kinase Domain Residues
%J -
%D 2019
%R https://doi.org/10.1021/acsmedchemlett.8b00546
%X The atypical protein kinase C-iota (PKC-¦É) enzyme is implicated in various cancers and has been put forward as an attractive target for developing anticancer therapy. A high concentration biochemical screen identified pyridine fragment weakly inhibiting PKC-¦É with IC50 = 424 ¦ÌM. Driven by structure¨Cactivity relationships and guided by docking hypothesis, the weakly bound fragment was eventually optimized into a potent inhibitor of PKC-¦É (IC50= 270 nM). Through the course of the optimization, an intermediate compound was crystallized with the protein, and careful analysis of the X-ray crystal structure revealed a unique binding mode involving the post-kinase domain (C-terminal tail) of PKC-¦É
%U https://pubs.acs.org/doi/10.1021/acsmedchemlett.8b00546