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Selectivity-determining residues in Plk1

Michael Kothe1, Darcy Kohls, Simon Low

  • 1Pfizer Global Research and Development, Research Technology Center, 620 Memorial Drive, Cambridge, MA 02139, USA.

Chemical Biology & Drug Design
|November 17, 2007
PubMed

Insights

Polo-like kinase 1 (PLK1) is crucial for cell cycle control and cancer. This study reveals the crystal structure of PLK1 with the inhibitor BI 2536, offering insights into drug design for cancer therapy.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Structural Biology

Background:

  • Polo-like kinase 1 (PLK1) is a key regulator of cell cycle progression.
  • Overexpression of PLK1 is linked to oncogenesis, making it a target for cancer intervention.
  • BI 2536 is a potent and selective PLK1 inhibitor in clinical trials.

Purpose of the Study:

  • To determine the co-crystal structure of Polo-like kinase 1 (PLK1) in complex with the inhibitor BI 2536.
  • To elucidate structural features contributing to BI 2536's potency and selectivity.
  • To provide a basis for structure-based drug design of PLK1 inhibitors.

Main Methods:

  • X-ray crystallography to obtain the co-crystal structure of PLK1 and BI 2536.
  • Analysis of the co-crystal structure to identify key interactions.
  • Evaluation of selectivity data for BI 2536 and related compounds.

Main Results:

  • The co-crystal structure of PLK1 with BI 2536 was determined.
  • The methoxy group of BI 2536 was identified as a critical specificity determinant.
  • A small pocket formed by Leu 132 in the PLK1 hinge region accommodates the methoxy group, enhancing selectivity against non-PLK kinases.

Conclusions:

  • The structure-based insights explain the high potency and selectivity of BI 2536.
  • The findings provide a framework for designing novel, specific PLK1 inhibitors for cancer therapy.
  • Understanding these interactions is crucial for developing targeted cancer treatments.

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