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Identification and Characterization of an Irreversible Inhibitor of CDK2
Univ Oxford, Dept Biochem, Oxford OX1 3QU, England..
Newcastle Univ, Sch Chem, Northern Inst Canc Res, Newcastle Canc Ctr, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England..
Newcastle Univ, Newcastle Canc Ctr, Northern Inst Canc Res, Sch Med, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England..
Newcastle Univ, Newcastle Canc Ctr, Northern Inst Canc Res, Sch Med, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England..
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2015 (English)In: Chemistry and Biology, ISSN 1074-5521, E-ISSN 1879-1301, Vol. 22, no 9, 1159-1164 p.Article in journal (Refereed) PublishedText
Abstract [en]

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-(Cyclo-hexylmethoxy)-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.

Place, publisher, year, edition, pages
2015. Vol. 22, no 9, 1159-1164 p.
National Category
Biochemistry and Molecular Biology
URN: urn:nbn:se:uu:diva-268711DOI: 10.1016/j.chembiol.2015.07.018ISI: 000364012100001PubMedID: 26320860OAI: diva2:878807
Swedish Research Council, 621-2013-5713EU, European Research Council
Available from: 2015-12-09 Created: 2015-12-09 Last updated: 2015-12-09Bibliographically approved

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Danielson, U. Helena
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