2. Academic Validation
  3. Identification and Characterization of an Irreversible Inhibitor of CDK2

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.
Elizabeth Anscombe 1,  Elisa Meschini 2,  Regina Mora-Vidal 3,  Mathew P Martin 3,  David Staunton 1,  Matthis Geitmann 4,  U Helena Danielson 5,  Will A Stanley 3,  Lan Z Wang 3,  Tristan Reuillon 2,  Bernard T Golding 6,  Celine Cano 2,  David R Newell 3,  Martin E M Noble 1,  Stephen R Wedge 3,  Jane A Endicott 7,  Roger J Griffin 2
Affiliations

Affiliations

  • 1 Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
  • 2 Newcastle Cancer Centre, Northern Institute for Cancer Research, School of Chemistry, Bedson Building, Newcastle University, Newcastle upon Tyne NE1 7RU, UK.
  • 3 Newcastle Cancer Centre, Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK.
  • 4 Beactica AB, Box 567, 751 22 Uppsala, Sweden.
  • 5 Beactica AB, Box 567, 751 22 Uppsala, Sweden; Department of Chemistry-BMC, Uppsala University, 751 23 Uppsala, Sweden.
  • 6 Newcastle Cancer Centre, Northern Institute for Cancer Research, School of Chemistry, Bedson Building, Newcastle University, Newcastle upon Tyne NE1 7RU, UK. Electronic address: bernard.golding@ncl.ac.uk.
  • 7 Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK. Electronic address: jane.endicott@ncl.ac.uk.
PMID: 26320860 DOI: 10.1016/j.chembiol.2015.07.018
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-18930
    CDK2抑制剂
    CDK
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