title: Identification and Characterization of an Irreversible Inhibitor of CDK2.
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.
authors: Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
authors: Elizabeth
authors: E
authors: Anscombe
authors: Newcastle Cancer Centre, Northern Institute for Cancer Research, School of Chemistry, Bedson Building, Newcastle University, Newcastle upon Tyne NE1 7RU, UK.
authors: Elisa
authors: E
authors: Meschini
authors: Newcastle Cancer Centre, Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK.
authors: Regina
authors: R
authors: Mora-Vidal
authors: Newcastle Cancer Centre, Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK.
authors: Mathew P
authors: MP
authors: Martin
authors: Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
authors: David
authors: D
authors: Staunton
authors: Beactica AB, Box 567, 751 22 Uppsala, Sweden.
authors: Matthis
authors: M
authors: Geitmann
authors: Beactica AB, Box 567, 751 22 Uppsala, Sweden; Department of Chemistry-BMC, Uppsala University, 751 23 Uppsala, Sweden.
authors: U Helena
authors: UH
authors: Danielson
authors: Newcastle Cancer Centre, Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK.
authors: Will A
authors: WA
authors: Stanley
authors: Newcastle Cancer Centre, Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK.
authors: Lan Z
authors: LZ
authors: Wang
authors: Newcastle Cancer Centre, Northern Institute for Cancer Research, School of Chemistry, Bedson Building, Newcastle University, Newcastle upon Tyne NE1 7RU, UK.
authors: Tristan
authors: T
authors: Reuillon
authors: 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.
authors: Bernard T
authors: BT
authors: Golding
authors: Newcastle Cancer Centre, Northern Institute for Cancer Research, School of Chemistry, Bedson Building, Newcastle University, Newcastle upon Tyne NE1 7RU, UK.
authors: Celine
authors: C
authors: Cano
authors: Newcastle Cancer Centre, Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK.
authors: David R
authors: DR
authors: Newell
authors: Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
authors: Martin E M
authors: ME
authors: Noble
authors: Newcastle Cancer Centre, Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK.
authors: Stephen R
authors: SR
authors: Wedge
authors: Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK. Electronic address: jane.endicott@ncl.ac.uk.
authors: Jane A
authors: JA
authors: Endicott
authors: Newcastle Cancer Centre, Northern Institute for Cancer Research, School of Chemistry, Bedson Building, Newcastle University, Newcastle upon Tyne NE1 7RU, UK.
authors: Roger J
authors: RJ
authors: Griffin
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D001665:Binding Sites; D001667:Binding, Competitive; D018360:Crystallography, X-Ray; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011687:Purines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000737:chemistry
chemical_list: C466914:NU6102; D047428:Protein Kinase Inhibitors; D011687:Purines; D013450:Sulfones; C009873:divinyl sulfone; D000255:Adenosine Triphosphate; D051357:Cyclin-Dependent Kinase 2