Exploring the PI3Kα and γ binding sites with 2,6-disubstituted isonicotinic derivatives

Using a homology model of PI3Kα based of PI3Kγ, a series of isonicotinic acid derivatives was designed and synthesized for studying the PI3Kα and γ active sites. A homology model of the p110α catalytic subunit of PI3Kα was generated from the p110γ crystal structure. Using this model, an isonicotinic...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2009-04, Vol.19 (8), p.2215-2219
Hauptverfasser:	Cherian, Philip T., Koikov, Leonid N., Wortman, Matthew D., Knittel, James J.
Format:	Artikel
Sprache:	eng
Schlagworte:	Binding Sites Catalytic Domain Class Ib Phosphatidylinositol 3-Kinase Class II Phosphatidylinositol 3-Kinases Crystallography, X-Ray Isoenzymes - antagonists & inhibitors Isoenzymes - chemistry Isoenzymes - metabolism Isonicotinic Acids - chemistry Isonicotinic Acids - metabolism Isonicotinic Acids - pharmacology Models, Molecular Morpholines - chemistry Phosphatidylinositol 3-Kinases - antagonists & inhibitors Phosphatidylinositol 3-Kinases - chemistry Phosphatidylinositol 3-Kinases - metabolism Protein Binding Pyridines - chemistry
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Zusammenfassung:	Using a homology model of PI3Kα based of PI3Kγ, a series of isonicotinic acid derivatives was designed and synthesized for studying the PI3Kα and γ active sites. A homology model of the p110α catalytic subunit of PI3Kα was generated from the p110γ crystal structure. Using this model, an isonicotinic scaffold was designed for chemically exploring the PI3Kα and γ binding sites. A focused library of derivatives was synthesized and tested. The morpholine acids 5a and 5b proved to be the most potent analogs.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2009.02.115