Progress in the development and application of small molecule inhibitors of bromodomain-acetyl-lysine interactions

Journal of Medicinal Chemistry
David S HewingsStuart J Conway

Abstract

Bromodomains, protein modules that recognize and bind to acetylated lysine, are emerging as important components of cellular machinery. These acetyl-lysine (KAc) "reader" domains are part of the write-read-erase concept that has been linked with the transfer of epigenetic information. By reading KAc marks on histones, bromodomains mediate protein-protein interactions between a diverse array of partners. There has been intense activity in developing potent and selective small molecule probes that disrupt the interaction between a given bromodomain and KAc. Rapid success has been achieved with the BET family of bromodomains, and a number of potent and selective probes have been reported. These compounds have enabled linking of the BET bromodomains with diseases, including cancer and inflammation, suggesting that bromodomains are druggable targets. Herein, we review the biology of the bromodomains and discuss the SAR for the existing small molecule probes. The biology that has been enabled by these compounds is summarized.

References

May 25, 1992·Nucleic Acids Research·S R HaynesI B Dawid
Oct 28, 1993·Nature·J C ChriviaR H Goodman
Dec 19, 1996·Nature·A J Bannister, Tony Kouzarides
Jul 15, 1999·Nature Structural Biology·F Winston, C David Allis
Jan 19, 2000·Nature·Brian D Strahl, C David Allis
Mar 16, 2000·The EMBO Journal·Tony Kouzarides
Aug 11, 2001·Science·T Jenuwein, C David Allis
Mar 26, 2002·FEBS Letters·L Zeng, Ming-Ming Zhou
Nov 7, 2002·Cell·Theodora AgaliotiDimitris Thanos
May 1, 1964·Proceedings of the National Academy of Sciences of the United States of America·V G ALLFREYA E MIRSKY
Jun 9, 2004·Trends in Cell Biology·Alejandra Loyola, Geneviève Almouzni
Nov 13, 2004·Philosophical Transactions. Series A, Mathematical, Physical, and Engineering Sciences·Nicholas J Westwood
Feb 24, 2005·Journal of the American Chemical Society·Lei ZengMing-Ming Zhou
May 18, 2005·Angewandte Chemie·Markus BielAthanassios Giannis
Feb 10, 2007·Cell·Zachary A Knight, Kevan M Shokat
Jun 28, 2007·Expert Opinion on Investigational Drugs·Madeleine Duvic, Jenny Vu
Aug 19, 2007·Oncogene·S MujtabaM-M Zhou
Nov 14, 2007·Epigenetics : Official Journal of the DNA Methylation Society·Robin Holliday
Dec 25, 2008·The Journal of Organic Chemistry·Gary A MolanderLauren E Kennedy
Feb 24, 2009·Nature Reviews. Molecular Cell Biology·Aline V ProbstGeneviève Almouzni
Oct 7, 2009·Proceedings of the National Academy of Sciences of the United States of America·Kazuki SasakiMinoru Yoshida
Oct 16, 2009·The Journal of Biological Chemistry·Friederike VollmuthMatthias Geyer
Dec 22, 2009·Organic & Biomolecular Chemistry·Stuart J ConwayAndrew B Holmes
Jan 30, 2010·Epigenetics : Official Journal of the DNA Methylation Society·David C BedfordPaul K Brindle
Apr 7, 2010·Cell Research·Zachary Charlop-PowersMing-Ming Zhou
Aug 18, 2010·Angewandte Chemie·Friederike Vollmuth, Matthias Geyer
Sep 28, 2010·Nature·Panagis FilippakopoulosJames E Bradner
Nov 12, 2010·Nature·Edwige NicodemeAlexander Tarakhovsky
Jan 29, 2011·Journal of the American Chemical Society·Guillermo Gerona-NavarroMing-Ming Zhou
Jan 29, 2011·Journal of Molecular Biology·Kathryn E GardnerBrian D Strahl
May 19, 2011·Nature Chemical Biology·Mark E Bunnage
Jun 15, 2011·Bioorganic & Medicinal Chemistry·Wolfgang Sippl, Manfred Jung
Jun 28, 2011·Expert Opinion on Investigational Drugs·Erin M Bertino, Gregory A Otterson
Aug 5, 2011·Nature·Johannes ZuberChristopher R Vakoc
Aug 20, 2011·Journal of Medicinal Chemistry·David S HewingsTom D Heightman
Sep 6, 2011·Cell·Jake E DelmoreConstantine S Mitsiades
Sep 29, 2011·Proceedings of the National Academy of Sciences of the United States of America·Jennifer A MertzRobert J Sims
Oct 1, 2011·Journal of Biomolecular Screening·Chun-wa Chung, Jason Witherington
Oct 11, 2011·Nature Cell Biology·Rui ZhaoDavid L Spector
Dec 6, 2011·Journal of Medicinal Chemistry·Paul BamboroughChun-wa Chung
Dec 6, 2011·Bioorganic & Medicinal Chemistry·Panagis FilippakopoulosStefan Knapp
Jan 27, 2012·Trends in Pharmacological Sciences·Rab K PrinjhaKevin Lee
Mar 6, 2012·Bioorganic & Medicinal Chemistry Letters·Olivier MirguetEdwige Nicodème
Mar 23, 2012·Bioorganic & Medicinal Chemistry Letters·Jonathan SealRab K Prinjha
Apr 14, 2012·Nature Reviews. Drug Discovery·Cheryl H ArrowsmithMatthieu Schapira
Apr 18, 2012·Proceedings of the National Academy of Sciences of the United States of America·Ballachanda N DevaiahDinah S Singer
May 16, 2012·Cancer Discovery·James D Watson
May 31, 2012·The Journal of Biological Chemistry·Guangtao ZhangMing-Ming Zhou
Jun 20, 2012·FEBS Letters·Panagis Filippakopoulos, Stefan Knapp
Sep 13, 2012·ACS Medicinal Chemistry Letters·Stuart J Conway

Citations

Apr 10, 2013·Epigenomics·Cassandra L Smith
Aug 20, 2014·Zeitschrift für Rheumatologie·A RammingA Jüngel
Jan 29, 2014·Future Medicinal Chemistry·Laura E JenningsStuart J Conway
May 29, 2013·FEBS Letters·Sandra SteinerAmedeo Caflisch
Feb 10, 2016·Proceedings of the National Academy of Sciences of the United States of America·Brandon L CroweMark P Foster
Jun 27, 2015·Proceedings of the National Academy of Sciences of the United States of America·Chiara PastoriClaes Wahlestedt
Nov 18, 2015·Journal of Medicinal Chemistry·F Anthony RomeroSteven R Magnuson
Feb 26, 2016·Journal of Medicinal Chemistry·Laetitia J MartinDarryl McConnell
Sep 21, 2015·Journal of Computer-aided Molecular Design·A R BradleyB D Marsden
May 18, 2016·ACS Medicinal Chemistry Letters·Alexander M TaylorBrian K Albrecht
Mar 17, 2016·Journal of Medicinal Chemistry·Andrea UnzueCristina Nevado
Aug 12, 2015·Journal of Chemical Information and Modeling·Ming KuangRuibo Wu
Jul 15, 2015·Experimental Hematology·Faisal Basheer, Brian J P Huntly
Sep 2, 2014·Current Opinion in Pharmacology·Julian Blagg, Paul Workman
Nov 23, 2013·Expert Opinion on Therapeutic Patents·Jean-Marc GarnierChristopher J Burns
Jun 5, 2015·Journal of Medicinal Chemistry·Andrea UnzueCristina Nevado
Mar 25, 2014·Biochimica Et Biophysica Acta·Steven Fletcher, Edward V Prochownik
Mar 30, 2013·European Journal of Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft Für Pharmazeutische Verfahrenstechnik E.V·Régis DelatouchePhilippe Bertrand
Jul 17, 2014·Drug Discovery Today. Technologies·Dafydd R Owen, John D Trzupek
May 25, 2016·Journal of Medicinal Chemistry·Terry D CrawfordAndrea G Cochran
Feb 15, 2017·Journal of Medicinal Chemistry·Zhiqing LiuJia Zhou
Oct 14, 2014·Frontiers in Genetics·Alejandro Cabezas-CruzRaymond J Pierce
Apr 5, 2017·Journal of Medicinal Chemistry·R Aldrin DennyEugene L Piatnitski Chekler
Feb 25, 2018·The Journal of Biological Chemistry·Grant R CampbellStephen A Spector
Jun 13, 2018·Chemical Record : an Official Publication of the Chemical Society of Japan ... [et Al.]·Yukihiro Itoh
Feb 6, 2014·ChemMedChem·Daniel GallenkampHilmar Weinmann
Nov 9, 2019·Physical Chemistry Chemical Physics : PCCP·Haiyang ZhongTingjun Hou
Jun 1, 2016·Journal of Biosciences·Balasundaram PadmanabhanShailesh Tripathi
Nov 1, 2018·Current Medicinal Chemistry·Victoria Lucia AlonsoEsteban Serra
Mar 21, 2013·Molecular BioSystems·Yukihiro ItohNaoki Miyata
Nov 26, 2013·Angewandte Chemie·Xavier LucasStefan Günther
Oct 28, 2017·PloS One·Xiaoxiao ZhangOlaf Wiest
Apr 25, 2019·Nature Communications·Qin WuStefan Knapp
Jan 11, 2016·ChemMedChem·Natalie H TheodoulouPhilip G Humphreys
Jul 6, 2019·Nature Reviews. Drug Discovery·Andrea G CochranRobert J Sims

Related Concepts

Acetylation
Metazoa
Histone H7
Enisyl
Nucleolar Proteins
Plasma Protein Binding Capacity
Post-Translational Protein Processing
Molecular Targeted Therapy
Acetylation
Malignant Neoplasms

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