학술논문
Pharmacological and functional comparison of the polo-like kinase family: insight into inhibitor and substrate specificity.
Document Type
Academic Journal
Author
Johnson EF; Cancer Research, Abbott Laboratories, AP9, 100 Abbott Park Road, Abbott Park, Illinois 60064, USA. eric.f.johnson@abbott.com; Stewart KD; Woods KW; Giranda VL; Luo Y
Source
Publisher: American Chemical Society Country of Publication: United States NLM ID: 0370623 Publication Model: Print-Electronic Cited Medium: Print ISSN: 0006-2960 (Print) Linking ISSN: 00062960 NLM ISO Abbreviation: Biochemistry Subsets: MEDLINE
Subject
Language
English
ISSN
0006-2960
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.