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

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

Affiliation

  • 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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