Targeted covalent inactivation of protein kinases by resorcylic acid lactone polyketides

Proceedings of the National Academy of Sciences of the United States of America
Andreas SchirmerDaniel V Santi

Abstract

Resorcylic acid lactones containing a cis-enone are susceptible to Michael addition reactions and are potent inhibitors of several protein kinases. A structural-bioinformatics analysis identified a conserved Cys residue in the ATP-binding site of the kinases reported to be inhibited by cis-enone resorcylic acid lactones but absent in those that are not. Mining of the kinome database revealed that a subset of some 46 kinases contained this Cys residue. Screening a panel of 124 kinases with the resorcylic acid lactone hypothemycin showed that 18 of 19 targets containing the conserved Cys were inhibited. Kinetic analyses showed time-dependent inhibition, a hallmark of covalent inactivation, and biochemical studies of the interaction of extracellular signal-regulated kinase (ERK)2 with hypothemycin confirmed covalent adduct formation. Resorcylic acid lactones are unique among kinase inhibitors in that they target mitogen-activated protein (MAP) kinase pathways at four levels: mitogen receptors, MAP kinase kinase (MEK)1/2 and ERK1/2, and certain downstream ERK substrates. Cell lines dependent on the activation of Tyr kinase mitogen receptor targets of the resorcylic acid lactones were unusually sensitive toward hypothemycin and show...Continue Reading

References

Jan 24, 1986·Nucleic Acids Research·D M Valenzuela, J Groffen
Sep 17, 1996·Proceedings of the National Academy of Sciences of the United States of America·C Y Huang, J E Ferrell
Sep 30, 1998·Proceedings of the National Academy of Sciences of the United States of America·D W FryE M Dobrusin
Dec 14, 1999·Japanese Journal of Cancer Research : Gann·H TanakaT Yoshioka
Mar 1, 2000·The Journal of Antibiotics·A DombrowskiM Goetz
Jun 18, 2002·Nature·Helen DaviesP Andrew Futreal
Dec 10, 2002·Science·G ManningS Sudarsanam
Jan 17, 2003·Leukemia·H QuentmeierH G Drexler
Jun 17, 2003·Proceedings of the National Academy of Sciences of the United States of America·John H GriffinRoger Briesewitz
Feb 16, 2005·Nature Biotechnology·Miles A FabianDavid J Lockhart
Apr 13, 2005·Biochemistry·James G Robertson
May 18, 2005·Proceedings of the National Academy of Sciences of the United States of America·Eunice L KwakDaniel A Haber
Jun 25, 2005·Chemistry & Biology·Zachary A Knight, Kevan M Shokat
Nov 8, 2005·Nature·David B SolitNeal Rosen
Feb 13, 2013·Clinical and Experimental Dermatology·G W M Millington

❮ Previous
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Citations

Mar 23, 2010·Journal of Computer-aided Molecular Design·Alberto Del RioGiulio Rastelli
Jul 16, 2013·Bioorganic & Medicinal Chemistry Letters·Keith R HornbergerBrianna Tokar
Oct 25, 2011·Chemical Reviews·Christopher J ThibodeauxHung-wen Liu
Apr 17, 2010·Journal of the American Chemical Society·Wenjun ZhangChristopher T Walsh
May 25, 2012·Journal of Medicinal Chemistry·Tjeerd Barf, Allard Kaptein
Jun 8, 2011·The Journal of Organic Chemistry·Bhavesh H PatelAnthony G M Barrett
Dec 24, 2008·Nature Reviews. Cancer·Jianming ZhangNathanael S Gray
Apr 2, 2011·Nature Reviews. Drug Discovery·Juswinder SinghAdrian Whitty
Apr 23, 2008·Proceedings of the National Academy of Sciences of the United States of America·Hui ZhouYi Tang
Feb 4, 2009·Assay and Drug Development Technologies·Karen M Kleman-LeyerRobert G Lowery
Oct 11, 2007·The Journal of Pharmacology and Experimental Therapeutics·Bettina M JensenAlasdair M Gilfillan
Mar 28, 2008·Annual Review of Biochemistry·Benjamin F CravattJohn W Kozarich
Sep 3, 2009·Molecular Cancer Therapeutics·Julien Viaud, Jeffrey R Peterson
Jun 21, 2008·Journal of Biomolecular Screening·Tony A KlinkRobert G Lowery
Nov 11, 2009·Journal of Biomolecular Screening·Johanna S BleesCurtis J Henrich
Oct 12, 2013·PloS One·Kinga MajchrzakMagdalena Król
May 8, 2009·Bioscience, Biotechnology, and Biochemistry·Takasumi KashimaKensuke Nabeta
Jul 16, 2013·ELife·Emily R Derbyshire, Jon Clardy
Jan 15, 2015·Future Medicinal Chemistry·Iain Kilty, Lyn H Jones
Jun 24, 2008·Journal of Structural Biology·Giulio RastelliDaniel V Santi
Nov 11, 2015·Journal of Proteome Research·Mingming DongHanfa Zou
Jun 12, 2013·Chemical Biology & Drug Design·Iain KiltyLyn H Jones
Jul 28, 2011·Chemical Biology & Drug Design·Roberta NoberiniElena B Pasquale
Jan 7, 2015·European Journal of Medicinal Chemistry·Weiyun ShenJinyan Dong
Jan 7, 2015·The Biochemical Journal·Fiona P BaileyPatrick A Eyers
Feb 27, 2013·Chemistry & Biology·Qingsong LiuNathanael S Gray
Jan 31, 2012·Chemistry & Biology·Tinghu ZhangNathanael S Gray
Aug 10, 2016·The Journal of Organic Chemistry·Rachelle QuachMargaret A Brimble
Jan 18, 2017·Future Medicinal Chemistry·Dominic P ByrnePatrick A Eyers
Oct 11, 2017·Angewandte Chemie·Apirat ChaikuadStefan Knapp
Aug 11, 2007·ChemMedChem·Brian R HearnDaniel V Santi
Aug 7, 2007·Angewandte Chemie·Pierre-Yves DakasNicolas Winssinger
May 22, 2008·Archiv der Pharmazie·Allan Wissner, Tarek S Mansour
Jul 14, 2010·Chembiochem : a European Journal of Chemical Biology·Sofia BarluengaNicolas Winssinger

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