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Chemistry & Biology 2015, 22, 1159–1164.pdf (1.71 MB)

Identification and characterization of an irreversible inhibitor of CDK2

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posted on 2023-06-09, 00:01 authored by Elizabeth Anscombe, Elisa Meschini, Regina Mora-Vidal, Mathew P Martin, David Staunton, Matthis Geitmann, U Helena Danielson, Will A Stanley, Lan Z Wang, Tristan Reuillon, Bernard T Golding, Celine Cano, David R Newell, Martin E M Noble, Stephen R Wedge, Jane A Endicott, Roger J Griffin
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.

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Publication status

  • Published

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  • Published version

Journal

Chemistry & Biology

ISSN

1074-5521

Publisher

Elsevier

Issue

9

Volume

22

Page range

1159-1164

Department affiliated with

  • Chemistry Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2016-01-15

First Open Access (FOA) Date

2016-01-15

First Compliant Deposit (FCD) Date

2016-01-15

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