Design and Structural Characterization of Potent and Selective Inhibitors of Phosphatidylinositol 4 Kinase IIIβ

• Published in: Journal of medicinal chemistry 2016-03, Vol.59 (5), p.1830-1839
• Main Authors: Rutaganira, Florentine U, Fowler, Melissa L, McPhail, Jacob A, Gelman, Michael A, Nguyen, Khanh, Xiong, Anming, Dornan, Gillian L, Tavshanjian, Brandon, Glenn, Jeffrey S, Shokat, Kevan M, Burke, John E
• Format: Article
• Language: English
• Subjects: Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Cell Line; Cell Survival - drug effects; Dose-Response Relationship, Drug; Drug Design; Hepacivirus - drug effects; Hepacivirus - physiology; Humans; Microbial Sensitivity Tests; Models, Molecular; Molecular Structure; Phosphotransferases (Alcohol Group Acceptor) - antagonists & inhibitors; Phosphotransferases (Alcohol Group Acceptor) - metabolism; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Structure-Activity Relationship; Virus Replication - drug effects
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.5b01311

Type III phosphatidylinositol 4-kinase (PI4KIIIβ) is an essential enzyme in mediating membrane trafficking and is implicated in a variety of pathogenic processes. It is a key host factor mediating replication of RNA viruses. The design of potent and specific inhibitors of this enzyme will be essential to define its cellular roles and may lead to novel antiviral therapeutics. We previously reported the PI4K inhibitor PIK93, and this compound has defined key functions of PI4KIIIβ. However, this compound showed high cross reactivity with class I and III PI3Ks. Using structure-based drug design, we have designed novel potent and selective (>1000-fold over class I and class III PI3Ks) PI4KIIIβ inhibitors. These compounds showed antiviral activity against hepatitis C virus. The co-crystal structure of PI4KIIIβ bound to one of the most potent compounds reveals the molecular basis of specificity. This work will be vital in the design of novel PI4KIIIβ inhibitors, which may play significant roles as antiviral therapeutics.