Pharmacological and Functional Comparison of the Polo-like Kinase Family:  Insight into Inhibitor and Substrate Specificity

• Published in: Biochemistry (Easton) Vol. 46; no. 33; pp. 9551 - 9563
• Main Authors: Johnson, Eric F, Stewart, Kent D, Woods, Keith W, Giranda, Vincent L, Luo, Yan
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 21.08.2007
• Subjects: Adenosine Triphosphate - chemistry; Amino Acid Sequence; Androstadienes - chemistry; Binding Sites; Cell Cycle Proteins - antagonists & inhibitors; Cell Cycle Proteins - chemistry; Humans; Models, Molecular; Molecular Sequence Data; Peptide Library; Polo-Like Kinase 1; Protein Conformation; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Protein Serine-Threonine Kinases - antagonists & inhibitors; Protein Serine-Threonine Kinases - chemistry; Proto-Oncogene Proteins - antagonists & inhibitors; Proto-Oncogene Proteins - chemistry; Pteridines - chemistry; Substrate Specificity; Wortmannin
• ISSN: 0006-2960; 1520-4995
• DOI: 10.1021/bi7008745

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.