- Design and Structural Characterization of Potent and Selective Inhibitors of Phosphatidylinositol 4 Kinase IIIβ
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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.
- 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.
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p. 1830 - 1839
(2016/03/22)
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- AMINOACID DERIVATIVES OF THIAZOLES AS INHIBITORS OF PI3 KINASE
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Compounds of formula (I) are inhibitors of PI3 kinase activity, and useful in treatment of, inter alia, autoimmune, inflammatory and proliferative diseases; wherein s is 0 or 1; U is hydrogen or halogen; X is -(C=O)-, or an optionally substituted divalent
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Page/Page column 27-28
(2010/11/29)
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- THIAZOLE DERIVATIVES AS INHIBITORS OF P13 KINASE
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Compounds of formula (I) are inhibitors of P13 kinase activity, and useful in treatment of, inter alia, autoimmune, inflammatory and proliferative diseases: wherein: s is 0 or 1; U is hydrogen or halogen; X is -(C=O), an optionally substituted divalent ph
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Page/Page column 34
(2008/06/13)
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- ENZYME AND RECEPTOR MODULATION
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Covalent conjugation of an alpha amino acid ester to a modulator of the activity of a target intracellular enzyme or receptor, wherein the ester group of the conjugate is hydrolysable by one or more intracellular carboxylesterase enzymes to the correspond
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Page/Page column 83
(2008/06/13)
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- 5-PHENYLTHIAZOLE DERIVATIVES AND USE AS PI3 KINASE INHIBITORS
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Compounds of Formula I in free or salt form, wherein R1,R2,R3,R4, and R5, have the meanings as indicated in the specification, are useful for treating diseases mediated by phosphatidylinositol 3-kinase. Pharmaceutical compositions that contain the compounds and processes for preparing the compounds are also described.
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Page/Page column 77
(2010/02/07)
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