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Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
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Structure-based discovery of cyclin-dependent protein kinase inhibitors

Mathew P Martin1, Jane A Endicott1, Martin E M Noble2

  • 1Newcastle Cancer Centre, Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, U.K.

Essays in Biochemistry
|November 10, 2017
PubMed

Insights

Cyclin-dependent kinase (CDK) inhibitors show promise for treating proliferative diseases like breast cancer. Structural data reveal how these inhibitors achieve affinity and selectivity for specific CDK targets.

Area of Science:

  • Molecular Biology
  • Drug Discovery
  • Structural Biology

Background:

  • Cyclin-dependent kinases (CDKs) regulate cell fate and their dysregulation is implicated in proliferative diseases.
  • The first CDK inhibitors have been approved for breast cancer treatment, highlighting their therapeutic potential.
  • Ongoing research aims to develop CDK inhibitors for broader clinical applications.

Purpose of the Study:

  • To review structural data illustrating inhibitor interactions with CDK family members.
  • To understand the basis of inhibitor affinity and selectivity for different CDKs.

Main Methods:

  • Review of existing structural data on CDK inhibitors.
  • Analysis of protein-ligand interactions and conformational dynamics.

Main Results:

  • Structural insights explain how inhibitors bind to CDKs with varying affinity and selectivity.
  • Selectivity is achieved by exploiting unique active site sequences or target CDK conformations.

Conclusions:

  • Understanding CDK-inhibitor interactions at a structural level is crucial for drug development.
  • Targeting specific CDK-inhibitor interactions can lead to more effective and selective cancer therapies.
Keywords:
CDKStructure-based drug designcell cyclekinase

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