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Identification and Characterization of an Irreversible Inhibitor of CDK2

DOI: 10.1016/j.chembiol.2015.07.018 DOI Help
PMID: 26320860 PMID Help

Authors: Elizabeth Anscombe (University of Oxford) , Elisa Meschini (Newcastle University) , Regina Mora-vidal (Newcastle University) , Mathew p. Martin (Newcastle University) , David Staunton (University of Oxford) , Matthis Geitmann (Beactica AB) , U. helena Danielson (Beactica AB) , Will a. Stanley (Newcastle University) , Lan z. Wang (Newcastle University) , Tristan Reuillon (Newcastle University) , Bernard t. Golding (Newcastle University) , Celine Cano (Newcastle University) , David r. Newell (Newcastle University) , Martin Noble (University of Oxford) , Stephen r. Wedge (Newcastle University) , Jane a. Endicott (University of Oxford) , Roger j. Griffin (Newcastle University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Chemistry & Biology , VOL 22 (9) , PAGES 1159 - 1164

State: Published (Approved)
Published: September 2015

Open Access Open Access

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.

Subject Areas: Biology and Bio-materials


Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)