Synthesis and Biological Evaluation of Novel Analogues of the Pan Class I Phosphatidylinositol 3-Kinase (PI3K) Inhibitor 2-(Difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzi

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• 作者：Gordon W. Rewcastle ; Swarna A. Gamage ; Jack U. Flanagan ; Raphael Frederick ; William A. Denny ; Bruce C. Baguley ; Philip Kestell ; Ripudaman Singh ; Jackie D. Kendall ; Elaine S. Marshall ; Claire L. Lill ; Woo-Jeong Lee ; Sharada Kolekar ; Christina M. Buchanan ; Stephen M. F. Jamieson ; Peter R. Shepherd
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：October 27, 2011
• 年：2011
• 卷：54
• 期：20
• 页码：7105-7126
• 全文大小：1309K
• 年卷期：v.54,no.20(October 27, 2011)
• ISSN：1520-4804

文摘

A structure鈥揳ctivity relationship (SAR) study of the pan class I PI 3-kinase inhibitor 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474) identified substitution at the 4 and 6 positions of the benzimidazole ring as having significant effects on the potency of substituted derivatives. The 6-amino-4-methoxy analogue displayed a greater than 1000-fold potency enhancement over the corresponding 6-aza-4-methoxy analogue against all three class Ia PI 3-kinase enzymes (p110伪, p110尾, and p110未) and also displayed significant potency against two mutant forms of the p110伪 isoform (H1047R and E545K). This compound was also evaluated in vivo against a U87MG human glioblastoma tumor xenograft model in Rag1^{鈥?鈥?/sup> mice, and at a dose of 50 mg/kg given by ip injection at a qd 脳 10 dosing schedule it dramatically reduced cancer growth by 81% compared to untreated controls.}