title: Exploring the PI3K alpha and gamma binding sites with 2,6-disubstituted isonicotinic derivatives.
abstract: A homology model of the p110alpha catalytic subunit of PI3Kalpha was generated from the p110gamma crystal structure. Using this model, an isonicotinic scaffold was designed for chemically exploring the PI3Kalpha and gamma binding sites. A focused library of derivatives was synthesized and tested. The morpholine acids 5a and 5b proved to be the most potent analogs.
authors.affiliation: The James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH 45267, USA.
authors.forename: Philip T
authors.initials: PT
authors.lastname: Cherian
authors.forename: Leonid N
authors.initials: LN
authors.lastname: Koikov
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Wortman
authors.forename: James J
authors.initials: JJ
authors.lastname: Knittel
mesh_terms: D001665:Binding Sites; D020134:Catalytic Domain; D058541:Class II Phosphatidylinositol 3-Kinases; D058544:Class Ib Phosphatidylinositol 3-Kinase; D018360:Crystallography, X-Ray; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D007539:Isonicotinic Acids / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D008958:Models, Molecular; D009025:Morpholines / Q000737:chemistry; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry* / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011485:Protein Binding; D011725:Pyridines / Q000737:chemistry
chemical_list: D058541:Class II Phosphatidylinositol 3-Kinases; D058544:Class Ib Phosphatidylinositol 3-Kinase; D007527:Isoenzymes; D007539:Isonicotinic Acids; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011725:Pyridines; C037574:morpholine; C023666:pyridine