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

Abstract:

: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.

journal_name

Biochemistry

journal_title

Biochemistry

authors

Johnson EF,Stewart KD,Woods KW,Giranda VL,Luo Y

doi

10.1021/bi7008745

subject

Has Abstract

pub_date

2007-08-21 00:00:00

pages

9551-63

issue

33

eissn

0006-2960

issn

1520-4995

journal_volume

46

pub_type

杂志文章