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Identification and Characterization of an Irreversible Inhibitor of CDK2.
- Source :
-
Chemistry & biology [Chem Biol] 2015 Sep 17; Vol. 22 (9), pp. 1159-64. Date of Electronic Publication: 2015 Aug 27. - Publication Year :
- 2015
-
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.<br /> (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Subjects :
- Adenosine Triphosphate metabolism
Binding Sites
Binding, Competitive
Crystallography, X-Ray
Cyclin-Dependent Kinase 2 chemistry
Cyclin-Dependent Kinase 2 metabolism
Drug Design
Humans
Models, Molecular
Protein Binding
Protein Kinase Inhibitors chemical synthesis
Purines chemical synthesis
Structure-Activity Relationship
Sulfones chemistry
Cyclin-Dependent Kinase 2 antagonists & inhibitors
Protein Kinase Inhibitors chemistry
Protein Kinase Inhibitors pharmacology
Purines chemistry
Purines pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1879-1301
- Volume :
- 22
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Chemistry & biology
- Publication Type :
- Academic Journal
- Accession number :
- 26320860
- Full Text :
- https://doi.org/10.1016/j.chembiol.2015.07.018