Identification and Characterization of an Irreversible Inhibitor of CDK2

被引：87

作者：

Anscombe, Elizabeth ^{[1
]}

Meschini, Elisa ^{[2
]}

Mora-Vidal, Regina ^{[3
]}

Martin, Mathew P. ^{[3
]}

Staunton, David ^{[1
]}

Geitmann, Matthis ^{[4
]}

Danielson, U. Helena ^{[4
]}

Stanley, Will A. ^{[3
]}

Wang, Lan Z. ^{[3
]}

Reuillon, Tristan ^{[2
]}

Golding, Bernard T. ^{[2
]}

Cano, Celine ^{[2
]}

Newell, David R. ^{[3
]}

Noble, Martin E. M. ^{[1
]}

Wedge, Stephen R. ^{[3
]}

Endicott, Jane A. ^{[1
]}

Griffin, Roger J. ^{[2
]}

机构：

[1] Univ Oxford, Dept Biochem, Oxford OX1 3QU, England

[2] Newcastle Univ, Sch Chem, Northern Inst Canc Res, Newcastle Canc Ctr, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England

[3] Newcastle Univ, Newcastle Canc Ctr, Northern Inst Canc Res, Sch Med, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England

[4] Uppsala Univ, Dept Chem BMC, S-75123 Uppsala, Sweden

来源：

CHEMISTRY & BIOLOGY | 2015年 / 22卷 / 09期

基金：

英国医学研究理事会; 瑞典研究理事会;

关键词：

PROTEIN-KINASE INHIBITORS; SYNTHETIC LETHALITY; CELL-CYCLE; CANCER; POTENT;

D O I：

10.1016/j.chembiol.2015.07.018

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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-(Cyclo-hexylmethoxy)-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.

引用

页码：1159 / 1164

页数：6

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