Pharmacological and functional comparison of the polo-like kinase family: insight into inhibitor and substrate specificity.
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.
Johnson
Eric F
EF
Cancer Research, Abbott Laboratories, AP9, 100 Abbott Park Road, Abbott Park, Illinois 60064, USA. eric.f.johnson@abbott.com
Stewart
Kent D
KD
Woods
Keith W
KW
Giranda
Vincent L
VL
Luo
Yan
Y
D000255:Adenosine Triphosphate / Q000737:chemistry; D000595:Amino Acid Sequence; D000730:Androstadienes / Q000737:chemistry; D001665:Binding Sites; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019151:Peptide Library; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D011621:Pteridines / Q000737:chemistry; D013379:Substrate Specificity; D000077191:Wortmannin; D000097869:Polo-Like Kinase 1
D000255:Adenosine Triphosphate; D000730:Androstadienes; D018797:Cell Cycle Proteins; D019151:Peptide Library; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011621:Pteridines; D000077191:Wortmannin; D000097869:Polo-Like Kinase 1; C518477:BI 2536