L-氨基酰基三嗪衍生物是亚型选择性PI3Kβ抑制剂，其作用于PI3Kβ的非保守性天冬氨酸862位点。
L-Aminoacyl-triazine derivatives are isoform-selective PI3Kβ inhibitors that target non-conserved Asp862 of PI3Kβ.
作者信息
Pinson Jo-Anne, Zheng Zhaohua, Miller Michelle S, Chalmers David K, Jennings Ian G, Thompson Philip E
机构信息
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville 3052 Australia.
出版信息
ACS Med Chem Lett. 2013 Feb 14;4(2):206-210. doi: 10.1021/ml300336j.
Abstract
A series of aminoacyl-triazine derivatives based upon the pan-PI3K inhibitor ZSTK474 were identified as potent and isoform selective inhibitors of PI3Kβ. The compounds showed selectivity based upon stereochemistry with L-amino acyl derivatives preferring PI3Kβ while their D-congeners favoured PI3Kδ. 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 PI3Kβ-selective inhibitors distinguishing this class from other reported PI3Kβ-selective inhibitors. The compounds show strong inhibition of cellular Akt phosphorylation and growth of PTEN-deficient MD-MBA-468 cells.
摘要
一系列基于泛PI3K抑制剂ZSTK474的氨酰基三嗪衍生物被鉴定为PI3Kβ的强效且亚型选择性抑制剂。这些化合物基于立体化学表现出选择性，L-氨酰基衍生物更倾向于PI3Kβ，而其D-异构体则有利于PI3Kδ。使用定点突变体研究了这种抑制作用的机制基础。一个天冬氨酸残基D862被确定为与PI3Kβ选择性抑制剂结合的关键参与者，这使该类抑制剂有别于其他已报道的PI3Kβ选择性抑制剂。这些化合物对细胞Akt磷酸化和PTEN缺陷的MD-MBA-468细胞的生长有强烈抑制作用。
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