Design and Structural Characterization of Potent and Selective Inhibitors of Phosphatidylinositol 4 Kinase III beta

作者：Rutaganira Florentine U; Fowler Melissa L; McPhail Jacob A; Gelman Michael A; Nguyen Khanh; Xiong Anming; Doman Gillian L; Tayshanjian Brandon; Glenn Jeffrey S; Shokat Kevan M^*; Burke John E^*

来源：Journal of Medicinal Chemistry, 2016, 59(5): 1830-1839.

DOI：10.1021/acs.jmedchem.5b01311

Type III phosphatidylinositol 4-kinase (PI4-KIII beta) 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 PI4KIII beta. 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) PI4KIII beta inhibitors. These compounds showed antiviral activity against hepatitis C virus. The co-crystal structure of PI4KIII beta bound to one of the most potent compounds reveals the molecular basis of specificity. This work will be vital in the design of novel PI4KIII beta inhibitors, which may play significant roles as antiviral therapeutics.

• 出版日期2016-3-10