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, David R, 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 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.

Item Type: Article
Schools and Departments: School of Life Sciences > Chemistry
Subjects: Q Science > QD Chemistry > QD0241 Organic chemistry
Depositing User: Tristan Reuillon
Date Deposited: 15 Jan 2016 15:48
Last Modified: 14 Mar 2017 23:25
URI: http://sro.sussex.ac.uk/id/eprint/59236

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