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-benzimidazole (ZSTK474)

被引：97

作者：

Rewcastle, Gordon W. ^{[1
,2
]}

Gamage, Swarna A. ^{[1
]}

Flanagan, Jack U. ^{[1
,2
]}

Frederick, Raphael ^{[1
,2
]}

Denny, William A. ^{[1
,2
]}

Baguley, Bruce C. ^{[1
,2
]}

Kestell, Philip ^{[1
]}

Singh, Ripudaman ^{[1
]}

Kendall, Jackie D. ^{[1
,2
]}

Marshall, Elaine S. ^{[1
]}

Lill, Claire L. ^{[1
]}

Lee, Woo-Jeong ^{[3
]}

Kolekar, Sharada ^{[3
]}

Buchanan, Christina M. ^{[2
,3
]}

Jamieson, Stephen M. F. ^{[1
,2
]}

Shepherd, Peter R. ^{[2
,3
]}

机构：

[1] Univ Auckland, Auckland Canc Soc Res Ctr, Sch Med & Hlth Sci, Auckland 1142, New Zealand

[2] Univ Auckland, Maurice Wilkins Ctr Mol Biodiscovery, Auckland 1142, New Zealand

[3] Univ Auckland, Dept Mol Med & Pathol, Sch Med & Hlth Sci, Auckland 1142, New Zealand

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2011年 / 54卷 / 20期

关键词：

PHOSPHOINOSITIDE; 3-KINASE; ANTITUMOR-ACTIVITY; PROTEIN-KINASE; BREAST-CANCER; MOUSE MODELS; TUMOR-GROWTH; PIK3CA GENE; POTENT; DISCOVERY; MECHANISMS;

D O I：

10.1021/jm200688y

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A structure activity 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 alpha, p110 beta, and p110 delta) and also displayed significant potency against two mutant forms of the p110 alpha isoform (H1047R and E545K). This compound was also evaluated in vivo against a U87MG human glioblastoma tumor xenograft model in Ragl(-/-) mice, and at a dose of 50 mg/kg given by ip injection at a qd x 10 dosing schedule it dramatically reduced cancer growth by 81% compared to untreated controls.

引用

页码：7105 / 7126

页数：22

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