Fragment-based Discovery of a Small-Molecule Protein Kinase C-iota Inhibitor Binding Post-kinase Domain Residues.
Basic Information
ID: ALA4400577
Journal: ACS Med Chem Lett
Title: Fragment-based Discovery of a Small-Molecule Protein Kinase C-iota Inhibitor Binding Post-kinase Domain Residues.
Authors: Kwiatkowski J, Baburajendran N, Poulsen A, Liu B, Tee DHY, Wong YX, Poh ZY, Ong EH, Dinie N, Cherian J, Jansson AE, Hill J, Keller TH, Hung AW.
Abstract: The atypical protein kinase C-iota (PKC-ι) 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-ι with IC50 = 424 μM. Driven by structure-activity relationships and guided by docking hypothesis, the weakly bound fragment was eventually optimized into a potent inhibitor of PKC-ι (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-ι.
CiteXplore: 30891133
DOI: 10.1021/acsmedchemlett.8b00546
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