Identification and Characterization of an Irreversible Inhibitor of CDK2

Chem Biol. 2015 Sep 17;22(9):1159-64. doi: 10.1016/j.chembiol.2015.07.018. Epub 2015 Aug 27.

Abstract

Irreversible inhibitors that modify cysteine or lysine residues within a protein kinase ATP binding site offer, through their distinctive mode of action, an alternative to ATP-competitive agents. 4-((6-(Cyclohexylmethoxy)-9H-purin-2-yl)amino)benzenesulfonamide (NU6102) is a potent and selective ATP-competitive inhibitor of CDK2 in which the sulfonamide moiety is positioned close to a pair of lysine residues. Guided by the CDK2/NU6102 structure, we designed 6-(cyclohexylmethoxy)-N-(4-(vinylsulfonyl)phenyl)-9H-purin-2-amine (NU6300), which binds covalently to CDK2 as shown by a co-complex crystal structure. Acute incubation with NU6300 produced a durable inhibition of Rb phosphorylation in SKUT-1B cells, consistent with it acting as an irreversible CDK2 inhibitor. NU6300 is the first covalent CDK2 inhibitor to be described, and illustrates the potential of vinyl sulfones for the design of more potent and selective compounds.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Binding Sites
  • Binding, Competitive
  • Crystallography, X-Ray
  • Cyclin-Dependent Kinase 2 / antagonists & inhibitors*
  • Cyclin-Dependent Kinase 2 / chemistry
  • Cyclin-Dependent Kinase 2 / metabolism
  • Drug Design
  • Humans
  • Models, Molecular
  • Protein Binding
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*
  • Purines / chemical synthesis
  • Purines / chemistry*
  • Purines / pharmacology*
  • Structure-Activity Relationship
  • Sulfones / chemistry

Substances

  • NU6102
  • Protein Kinase Inhibitors
  • Purines
  • Sulfones
  • divinyl sulfone
  • Adenosine Triphosphate
  • Cyclin-Dependent Kinase 2

Associated data

  • PDB/5CYI