l-Aminoacyl-triazine Derivatives Are Isoform-Selective PI3K尾 Inhibitors That Target Nonconserved Asp862 of PI3K尾
详细信息 查看全文
- 作者：Jo-Anne Pinson ; Zhaohua Zheng ; Michelle S. Miller ; David K. Chalmers ; Ian G. Jennings ; Philip E. Thompson
- 刊名：ACS Medicinal Chemistry Letters
- 出版年：2013
- 出版时间：February 14, 2013
- 年：2013
- 卷：4
- 期：2
- 页码：206-210
- 全文大小：251K
- 年卷期：v.4,no.2(February 14, 2013)
- ISSN：1948-5875
文摘
A series of aminoacyl-triazine derivatives based upon the pan-PI3K inhibitor ZSTK474 were identified as potent and isoform-selective inhibitors of PI3K尾. The compounds showed selectivity based upon stereochemistry with l-amino acyl derivatives preferring PI3K尾, while their d-congeners favored PI3K未. 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尾-selective inhibitors, distinguishing this class from other reported PI3K尾-selective inhibitors. The compounds show strong inhibition of cellular Akt phosphorylation and growth of PTEN-deficient MD-MBA-468 cells.