1. Development of isoform selective PI3-kinase inhibitors as pharmacological tools for elucidating the PI3K pathway.
- Author
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Bruce I, Akhlaq M, Bloomfield GC, Budd E, Cox B, Cuenoud B, Finan P, Gedeck P, Hatto J, Hayler JF, Head D, Keller T, Kirman L, Leblanc C, Le Grand D, McCarthy C, O'Connor D, Owen C, Oza MS, Pilgrim G, Press NE, Sviridenko L, and Whitehead L
- Subjects
- Animals, Catalytic Domain, Female, Humans, Mice, Models, Molecular, Phosphatidylinositol 3-Kinases chemistry, Phosphatidylinositol 3-Kinases metabolism, Protein Isoforms antagonists & inhibitors, Protein Isoforms chemistry, Protein Isoforms metabolism, Protein Kinase Inhibitors pharmacokinetics, Rats, Signal Transduction drug effects, Thiazoles pharmacokinetics, Phosphoinositide-3 Kinase Inhibitors, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors pharmacology, Thiazoles chemistry, Thiazoles pharmacology
- Abstract
Using a parallel synthesis approach to target a non-conserved region of the PI3K catalytic domain a pan-PI3K inhibitor 1 was elaborated to provide alpha, delta and gamma isoform selective Class I PI3K inhibitors 21, 24, 26 and 27. The compounds had good cellular activity and were selective against protein kinases and other members of the PI3K superfamily including mTOR and DNA-PK., (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- Published
- 2012
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