title: Selectivity-determining residues in Plk1.
abstract: Polo-like kinase 1 is an important regulator of cell cycle progression whose over-expression is often associated with oncogenesis. Polo-like kinase 1 hence represents an attractive target for cancer intervention. BI 2536 (Boehringer Ingelheim, Ingelheim, Germany), a Polo-like kinase 1 inhibitor currently in clinical trials, exhibits nanomolar potency against Polo-like kinase isoforms and high selectivity against other kinases. We have previously published the crystal structures of the Polo-like kinase 1 domain in complex with AMPPNP and an Aurora A inhibitor. In this work, we present the co-crystal structure of Polo-like kinase 1 with BI 2536. The structure, in combination with selectivity data for BI 2536 and related compounds, illustrates important features for potency and selectivity. In particular, we show that the methoxy group of BI 2536 is an important specificity determinant against non-Polo-like kinases by taking advantage of a small pocket generated by Leu 132 in the hinge region of Polo-like kinase 1. The work presented here provides a framework for structure-based drug design of Polo-like kinase 1-specific inhibitors.
authors.affiliation: Pfizer Global Research and Development, Research Technology Center, 620 Memorial Drive, Cambridge, MA 02139, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Kothe
authors.forename: Darcy
authors.initials: D
authors.lastname: Kohls
authors.forename: Simon
authors.initials: S
authors.lastname: Low
authors.forename: Rocco
authors.initials: R
authors.lastname: Coli
authors.forename: Glen R
authors.initials: GR
authors.lastname: Rennie
authors.forename: Frederic
authors.initials: F
authors.lastname: Feru
authors.forename: Cyrille
authors.initials: C
authors.lastname: Kuhn
authors.forename: Yuan-Hua
authors.initials: YH
authors.lastname: Ding
mesh_terms: D000266:Adenylyl Imidodiphosphate / Q000737:chemistry; D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D002986:Clinical Trials as Topic; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology; D011485:Protein Binding / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D017434:Protein Structure, Tertiary / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011621:Pteridines / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D000097869:Polo-Like Kinase 1
chemical_list: D000266:Adenylyl Imidodiphosphate; D018797:Cell Cycle Proteins; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011621:Pteridines; D000097869:Polo-Like Kinase 1; C518477:BI 2536