4flh
Crystal structure of human PI3K-gamma in complex with AMG511Crystal structure of human PI3K-gamma in complex with AMG511
Structural highlights
Publication Abstract from PubMedThe phosphoinositide 3-kinase family catalyzes the phosphorylation of phosphatidylinositol-4,5-diphosphate (PIP2) to phosphatidylinositol-3,4,5-triphosphate (PIP3), a secondary messenger which plays a critical role in important cellular functions such as metabolism, cell growth, and cell survival. Our efforts to identify potent, efficacious, and orally available PI3K inhibitors as potential cancer therapeutics have resulted in the discovery of 4-(2-((6-methoxypyridin-3-yl)amino)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)p yridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (1). In this report, we describe the optimization of compound 1, which led to the design and synthesis of pyridyl-triazine 31, a potent pan inhibitor of class I PI3Ks with a superior pharmacokinetic profile. Compound 31 was shown to potently block the targeted PI3K pathway in a mouse liver pharmacodynamic model and inhibit tumor growth in a U87 MG glioblastoma xenograft model. Based on its excellent in vivo efficacy and pharmacokinetic profile, compound 31 was selected for further evaluation as a clinical candidate and was designated AMG 511. Selective Class I Phosphoinositide 3-Kinase (PI3K) Inhibitors: Optimization of a Series of Pyridyl-triazines Leading to the Identification of a Clinical Candidate, AMG 511.,Norman MH, Liu L, Andrews K, Bo Y, Booker S, Caenepeel S, Cee VJ, D'Angelo ND, Freeman DJ, Herberich B, Hong FT, Jackson C, Jiang J, Lannman B, McCarter JD, Mullady E, Nishimura N, Pettus LH, Reed A, San Miguel T, Smith A, Stec MM, Tadesse S, Tasker A, Aidasani D, Zhu S, Subramanian R, Tamayo NA, Wang L, Whittington DA, Wu B, Wu T, Wurz RP, Yang K, Zalameda L, Zhang N, Hughes P J Med Chem. 2012 Aug 16. PMID:22897589[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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