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Fragment-based Discovery of a Small-Molecule Protein Kinase C-iota Inhibitor Binding Post-kinase Domain Residues.

ABSTRACT: The atypical protein kinase C-iota (PKC-?) 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-? with IC50 = 424 ?M. Driven by structure-activity relationships and guided by docking hypothesis, the weakly bound fragment was eventually optimized into a potent inhibitor of PKC-? (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-?.

SUBMITTER: Kwiatkowski J

PROVIDER: S-EPMC6421525 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Fragment-based Discovery of a Small-Molecule Protein Kinase C-iota Inhibitor Binding Post-kinase Domain Residues.

Kwiatkowski Jacek J Baburajendran Nithya N Poulsen Anders A Liu Boping B Tee Doris Hui Ying DHY Wong Yun Xuan YX Poh Zhi Ying ZY Ong Esther Hq EH Dinie Nurul N Cherian Joseph J Jansson Anna Elisabet AE Hill Jeffrey J Keller Thomas H TH Hung Alvin W AW

ACS medicinal chemistry letters 20190215 3

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 IC<sub>50</sub> = 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 (IC<sub>50</sub>= 270 nM). Through the course of ...[more]

PMID: 30891133

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