Exploring the PI3K alpha and gamma binding sites with 2,6-disubstituted isonicotinic derivatives.
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.
Cherian
Philip T
PT
The James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH 45267, USA.
Koikov
Leonid N
LN
Wortman
Matthew D
MD
Knittel
James J
JJ
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
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