Fragment-Based Drug Discovery of Potent Protein Kinase C Iota Inhibitors.

Abstract

Protein kinase C iota (PKC-ι) is an atypical kinase implicated in the promotion of different cancer types. A biochemical screen of a fragment library has identified several hits from which an azaindole-based scaffold was chosen for optimization. Driven by a structure-activity relationship and supported by molecular modeling, a weakly bound fragment was systematically grown into a potent and selective inhibitor against PKC-ι.

• Authors: Jacek Kwiatkowski, Boping Liu, Doris Hui Ying Tee, Guoying Chen, Nur Huda Binte Ahmad, Yun Xuan Wong, Zhi Ying Poh, Shi Hua Ang, Eldwin Sum Wai Tan, Esther Hq Ong, Nurul Dinie, Anders Poulsen, Vishal Pendharkar, Kanda Sangthongpitag, May Ann Lee, Sugunavathi Sepramaniam, Soo Yei Ho, Joseph Cherian, Jeffrey Hill, Thomas H Keller, Alvin W Hung
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 61 Issue 10 Pg. 4386-4396 (05 24 2018) ISSN: 1520-4804 [Electronic] United States
• PMID: 29688013 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Isoenzymes
• Protein Kinase Inhibitors
• Protein Kinase C
• protein kinase C lambda

Topics

• Carcinoma, Hepatocellular (drug therapy, pathology)
• Cell Proliferation (drug effects)
• Humans
• Isoenzymes (antagonists & inhibitors)
• Liver Neoplasms (drug therapy, pathology)
• Models, Molecular
• Molecular Structure
• Protein Conformation
• Protein Kinase C (antagonists & inhibitors)
• Protein Kinase Inhibitors (chemistry, pharmacology)
• Tumor Cells, Cultured