Pharmacological and functional comparison of the polo-like kinase family: Insight into inhibitor and substrate specificity

被引：102

作者：

Johnson, Eric F. ^{[1
]}

Stewart, Kent D. ^{[1
]}

Woods, Keith W. ^{[1
]}

Giranda, Vincent L. ^{[1
]}

Luo, Yan ^{[1
]}

机构：

[1] Abbott Labs, Canc Res, Abbott Pk, IL 60064 USA

来源：

BIOCHEMISTRY | 2007年 / 46卷 / 33期

关键词：

D O I：

10.1021/bi7008745

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

PLK1 (polo-like kinase 1) is a key mitotic kinase and a therapeutic target in the treatment of proliferative diseases. Here we investigate the relative substrate specificity and pharmacological relatedness of PLK1, -2, -3, and -4 that together comprise a conserved family of Ser/Thr kinases (PLK family). We report consensus substrate sequences for PLK2, -3, and -4 and an expanded consensus sequence for PLK1, which we use to design an optimal peptide substrate, PLKtide. We report inhibitory activity for the entire PLK family across a diverse set of small-molecule ATP-competitive inhibitors including several clinical compounds. With respect to both substrate and ATP-site specificity, highest similarity is observed between PLK2 and PLK3, PLK1 is next most similar, and PLK4 is least similar. Further, we have identified and report time-dependent inhibition by two potent and selective PLK inhibitors.

引用

页码：9551 / 9563

页数：13

共 67 条

[1]

ANDREWS CW, 2004, Patent No. 2004014899

[2]

BAHASSI M, 1994, ONCOGENE, V23, P2658

[3] Polo-like kinases and the orchestration of cell division [J].