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

  • ACS Med Chem Lett. 2019 Feb 15;10(3):318-323. doi: 10.1021/acsmedchemlett.8b00546.
Jacek Kwiatkowski  1 ,  Nithya Baburajendran  1 ,  Anders Poulsen  1 ,  Boping Liu  1 ,  Doris Hui Ying Tee  1 ,  Yun Xuan Wong  1 ,  Zhi Ying Poh  1 ,  Esther Hq Ong  1 ,  Nurul Dinie  1 ,  Joseph Cherian  1 ,  Anna Elisabet Jansson  1 ,  Jeffrey Hill  1 ,  Thomas H Keller  1 ,  Alvin W Hung  1
Affiliations
  • 1. Experimental Therapeutics Centre, Agency for Science, Technology and Research (ASTAR), 11 Biopolis Way, Helios #03-10/11, Singapore 138667, Singapore.
PMID: 30891133 DOI: 10.1021/acsmedchemlett.8b00546
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.

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