L-Aminoacyl-triazine Derivatives Are Isoform-Selective PI3Kβ Inhibitors That Target Nonconserved Asp862 of PI3Kβ

被引：27

作者：

Pinson, Jo-Anne ^{[1
]}

Zheng, Zhaohua ^{[1
]}

Miller, Michelle S. ^{[1
]}

Chalmers, David K. ^{[1
]}

Jennings, Ian G. ^{[1
]}

Thompson, Philip E. ^{[1
]}

机构：

[1] Monash Univ, Monash Inst Pharmaceut Sci, Parkville, Vic 3052, Australia

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2013年 / 4卷 / 02期

基金：

英国医学研究理事会; 美国国家卫生研究院;

关键词：

PI3; kinase; p110; beta; ZSTK474; cancer; ANTITUMOR-ACTIVITY; CLASS-I; 3-KINASE; DISCOVERY; SERIES; OPTIMIZATION; PHOSPHATASE; CAL-101; PATHWAY; MODELS;

D O I：

10.1021/ml300336j

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of aminoacyl-triazine derivatives based upon the pan-PI3K inhibitor ZSTK474 were identified as potent and isoform-selective inhibitors of PI3K beta. The compounds showed selectivity based upon stereochemistry with L-amino acyl derivatives preferring PI3K beta, while their D-congeners favored PI3K delta. The mechanistic basis of this inhibition was studied using site-directed mutants. One Asp residue, D862, was identified as a critical participant in binding to the PI3K beta-selective inhibitors, distinguishing this class from other reported PI3K beta-selective inhibitors. The compounds show strong inhibition of cellular Akt phosphorylation and growth of PTEN-deficient MD-MBA-468 cells.

引用

页码：206 / 210

页数：5

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