Identification and Characterization of an Irreversible Inhibitor of CDK2

Chemistry & Biology
Elizabeth AnscombeRoger J Griffin

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.

References

Aug 1, 1986·Annals of Internal Medicine·N H ShearW Kalow
Sep 24, 2002·Nature Structural Biology·Thomas G DaviesHayley J Whitfield
Jul 9, 2004·Journal of Medicinal Chemistry·Ian R HardcastleHayley J Whitfield
Sep 1, 1994·Acta Crystallographica. Section D, Biological Crystallography·UNKNOWN Collaborative Computational Project, Number 4
May 1, 1997·Acta Crystallographica. Section D, Biological Crystallography·G N MurshudovE J Dodson
Apr 14, 2006·Current Topics in Medicinal Chemistry·Radim VicikTanja Schirmeister
May 4, 2006·Journal of the American Chemical Society·Roger J GriffinBernard T Golding
Dec 24, 2008·Nature Reviews. Cancer·Jianming ZhangNathanael S Gray
Feb 25, 2009·Nature Reviews. Cancer·Marcos Malumbres, Mariano Barbacid
Aug 1, 2007·Journal of Applied Crystallography·Airlie J McCoyRandy J Read
Apr 13, 2010·Acta Crystallographica. Section D, Biological Crystallography·P EmsleyK Cowtan
May 10, 2011·Annual Review of Biochemistry·Arvin C Dar, Kevan M Shokat
May 17, 2011·European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)·Huw D ThomasDavid R Newell
Jan 18, 2012·ACS Chemical Biology·Mathew P MartinErnst Schönbrunn
Apr 5, 2012·Proceedings of the National Academy of Sciences of the United States of America·Dai HoriuchiAndrei Goga
May 25, 2012·Journal of Medicinal Chemistry·Tjeerd Barf, Allard Kaptein
Jul 18, 2012·Proceedings of the National Academy of Sciences of the United States of America·Christine K ChengQi-Wen Fan
Dec 1, 2012·Nature Reviews. Drug Discovery·Malini Guha
Jul 19, 2013·Development·Shuhui Lim, Philipp Kaldis
Nov 13, 2013·Proceedings of the National Academy of Sciences of the United States of America·Dariush EtemadmoghadamDavid D L Bowtell
Jul 22, 2014·Nature·Nicholas KwiatkowskiNathanael S Gray

❮ Previous
Next ❯

Citations

Oct 19, 2016·Nature Chemical Biology·Gizem AkçayQibin Su
Oct 25, 2016·Future Medicinal Chemistry·Tinghan LiZhiyu Li
Nov 23, 2016·Scientific Reports·Karine NormandinVincent Archambault
May 20, 2017·Cell Cycle·Vincent Archambault, Karine Normandin
Mar 17, 2018·Nature Reviews. Drug Discovery·Fleur M Ferguson, Nathanael S Gray
Oct 11, 2017·Angewandte Chemie·Apirat ChaikuadStefan Knapp
Apr 13, 2018·Angewandte Chemie·Lyn H Jones
Mar 1, 2019·ChemMedChem·Avick Kumar GhoshWenshe Ray Liu
Jun 22, 2019·Chemical Communications : Chem Comm·Jiraborrirak CharoenpattarapreedaDavid R Spring
Dec 14, 2019·Chembiochem : a European Journal of Chemical Biology·Samuel E Dalton, Sebastien Campos
Aug 31, 2017·Angewandte Chemie·Jonathan PettingerMatthew D Cheeseman
Apr 1, 2020·Chemical Society Reviews·Ayah AbdeldayemPatrick T Gunning
May 18, 2020·Angewandte Chemie·Mingxing TengNathanael S Gray
Feb 23, 2017·Angewandte Chemie·Jonathan PettingerMatthew D Cheeseman
Apr 6, 2018·Chemical Society Reviews·Richard Lonsdale, Richard A Ward
Nov 15, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Gaomin Zhang, Yujie Ren
Nov 10, 2017·Essays in Biochemistry·Mathew P MartinMartin E M Noble
Jan 12, 2019·Annual Review of Biochemistry·Adolfo Cuesta, Jack Taunton
Dec 5, 2020·Future Medicinal Chemistry·Elena De Vita
Dec 20, 2015·Molecular Cancer Research : MCR·Rakesh DachineniG Jayarama Bhat
Jan 15, 2019·European Journal of Medicinal Chemistry·Weiyan ChengQuancheng Kan
Sep 4, 2019·Bioorganic & Medicinal Chemistry Letters·Concepción Sánchez-MartínezAlfonso de Dios
Jan 21, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Mohammad M Al-SaneaMohamed A Abdelgawad
Jan 23, 2021·RSC Medicinal Chemistry·Christopher J MathesonCéline Cano
Mar 13, 2021·European Journal of Medicinal Chemistry·Josef JansaVladimír Kryštof
May 19, 2021·The Journal of Organic Chemistry·Gregory B CravenAlan Armstrong
Jul 27, 2021·Frontiers in Cell and Developmental Biology·Sunday OkutachiDaniel Abankwa
Dec 14, 2018·Journal of Medicinal Chemistry·Solomon TadesseShudong Wang
Dec 13, 2017·Journal of the American Chemical Society·Samuel E DaltonSebastien Campos
May 17, 2019·Journal of Medicinal Chemistry·Luca GambiniMaurizio Pellecchia
Mar 26, 2019·Journal of Chemical Information and Modeling·Laurent HofferPhilippe Roche
Jun 26, 2018·Journal of Medicinal Chemistry·Carlo BaggioMaurizio Pellecchia
Sep 21, 2018·Journal of Medicinal Chemistry·Radek JordaVladimír Kryštof
Sep 1, 2021·European Journal of Medicinal Chemistry·Francesca FerlenghiMarco Mor

❮ Previous
Next ❯

Methods Mentioned

BETA
xenografts
surface
biosensor
size-exclusion chromatography

Software Mentioned

Coot
CCP4i2
CCP4
REFMAC

Related Concepts

Related Feeds

Biosensors for Cancer Detection

Biosensors are devices that are designed to detect a specific biological analyte by essentially converting a biological entity (ie, protein, DNA, RNA) into an electrical signal that can be detected and analyzed. The use of biosensors in cancer detection and monitoring holds vast potential. Biosensors can be designed to detect emerging cancer biomarkers and to determine drug effectiveness at various target sites. Biosensor technology has the potential to provide fast and accurate detection, reliable imaging of cancer cells, and monitoring of angiogenesis and cancer metastasis, and the ability to determine the effectiveness of anticancer chemotherapy agents.

Related Papers

Bioorganic & Medicinal Chemistry Letters
Douglas S WilliamsonChristopher J Torrance
Bioorganic & Medicinal Chemistry Letters
Dominique LesuisseThomas Rooney
Bioorganic & Medicinal Chemistry Letters
Raymond V FuciniWenjin Yang
© 2021 Meta ULC. All rights reserved