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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Adenylyl Imidodiphosphate / chemistry
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Animals
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Cell Cycle / drug effects
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Cell Cycle Proteins / antagonists & inhibitors*
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Cell Cycle Proteins / chemistry
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Clinical Trials as Topic
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Crystallography, X-Ray
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Drug Design
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Humans
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Models, Molecular
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Neoplasm Proteins / antagonists & inhibitors*
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Neoplasm Proteins / chemistry
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Neoplasms / drug therapy
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Neoplasms / enzymology
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Polo-Like Kinase 1
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Protein Binding / physiology
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Protein Kinase Inhibitors / chemistry*
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Protein Kinase Inhibitors / pharmacology
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Protein Kinase Inhibitors / therapeutic use
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / chemistry
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Protein Structure, Tertiary / physiology
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Proto-Oncogene Proteins / antagonists & inhibitors*
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Proto-Oncogene Proteins / chemistry
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Pteridines / chemistry*
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Pteridines / pharmacology
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Pteridines / therapeutic use
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Structure-Activity Relationship
Substances
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BI 2536
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Cell Cycle Proteins
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Neoplasm Proteins
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins
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Pteridines
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Adenylyl Imidodiphosphate
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Protein Serine-Threonine Kinases