Structural Basis of Wee Kinases Functionality and Inactivation by Diverse Small Molecule Inhibitors

J Med Chem. 2017 Sep 28;60(18):7863-7875. doi: 10.1021/acs.jmedchem.7b00996. Epub 2017 Sep 14.


Members of the Wee family of kinases negatively regulate the cell cycle via phosphorylation of CDK1 and are considered potential drug targets. Herein, we investigated the structure-function relationship of human Wee1, Wee2, and Myt1 (PKMYT1). Purified recombinant full-length proteins and kinase domain constructs differed substantially in phosphorylation states and catalytic competency, suggesting complex mechanisms of activation. A series of crystal structures reveal unique features that distinguish Wee1 and Wee2 from Myt1 and establish the structural basis of differential inhibition by the widely used Wee1 inhibitor MK-1775. Kinome profiling and cellular studies demonstrate that, in addition to Wee1 and Wee2, MK-1775 is an equally potent inhibitor of the polo-like kinase PLK1. Several previously unrecognized inhibitors of Wee kinases were discovered and characterized. Combined, the data provide a comprehensive view on the catalytic and structural properties of Wee kinases and a framework for the rational design of novel inhibitors thereof.

MeSH terms

  • Cell Cycle Proteins / antagonists & inhibitors*
  • Cell Cycle Proteins / chemistry
  • Cell Cycle Proteins / metabolism
  • Humans
  • Membrane Proteins / antagonists & inhibitors*
  • Membrane Proteins / chemistry
  • Membrane Proteins / metabolism
  • Molecular Docking Simulation
  • Nuclear Proteins / antagonists & inhibitors*
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / metabolism
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein Serine-Threonine Kinases / chemistry
  • Protein Serine-Threonine Kinases / metabolism
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / chemistry
  • Protein-Tyrosine Kinases / metabolism
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology
  • Pyrimidinones
  • Small Molecule Libraries / chemistry*
  • Small Molecule Libraries / pharmacology*


  • Cell Cycle Proteins
  • Membrane Proteins
  • Nuclear Proteins
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyrimidines
  • Pyrimidinones
  • Small Molecule Libraries
  • Wee2 protein, human
  • Protein-Tyrosine Kinases
  • WEE1 protein, human
  • PKMYT1 protein, human
  • Protein Serine-Threonine Kinases
  • adavosertib