Identification and Characterization of an Irreversible Inhibitor of CDK2

Anscombe, Elizabeth, Meschini, Elisa, Mora-Vidal, Regina, Martin, Mathew P., Staunton, David, Geitmann, Matthis, Danielson, U. Helena, Stanley, Will A., Wang, Lan Z., Reuillon, Tristan, Golding, Bernard T., Cano, Celine, Newell, Herbie, Noble, Martin E.M., Wedge, Stephen R., Endicott, Jane A. and Griffin, Roger J. (2015) Identification and Characterization of an Irreversible Inhibitor of CDK2. Chemistry & Biology, 22 (9). pp. 1159-1164. ISSN 1074-5521

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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 SKUT1B 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

Item Type: Article
Divisions: Faculty of Health Sciences and Wellbeing
Faculty of Health Sciences and Wellbeing > FHSW Executive
Depositing User: Michelle Marshall
Date Deposited: 21 Aug 2019 15:26
Last Modified: 17 Sep 2020 15:59
URI: http://sure.sunderland.ac.uk/id/eprint/11054

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