Discovery and characterization of small molecule inhibitors of the BET family bromodomains

Journal of Medicinal Chemistry
Chun-Wa ChungEdwige Nicodeme


Epigenetic mechanisms of gene regulation have a profound role in normal development and disease processes. An integral part of this mechanism occurs through lysine acetylation of histone tails which are recognized by bromodomains. While the biological and structural characterization of many bromodomain containing proteins has advanced considerably, the therapeutic tractability of this protein family is only now becoming understood. This paper describes the discovery and molecular characterization of potent (nM) small molecule inhibitors that disrupt the function of the BET family of bromodomains (Brd2, Brd3, and Brd4). By using a combination of phenotypic screening, chemoproteomics, and biophysical studies, we have discovered that the protein-protein interactions between bromodomains and acetylated histones can be antagonized by selective small molecules that bind at the acetylated lysine recognition pocket. X-ray crystal structures of compounds bound into bromodomains of Brd2 and Brd4 elucidate the molecular interactions of binding and explain the precisely defined stereochemistry required for activity.


Jul 16, 2003·Molecular and Cellular Biology·Christophe Pivot-PajotSaadi Khochbin
Sep 30, 2004·Organic & Biomolecular Chemistry·Mariano CastroMark Ladlow
Oct 16, 2004·Circulation Research·Philip J BarterAlan M Fogelman
Dec 2, 2004·Acta Crystallographica. Section D, Biological Crystallography·Paul Emsley, Kevin Cowtan
Feb 24, 2005·Journal of the American Chemical Society·Lei ZengMing-Ming Zhou
Feb 3, 2007·Nature Reviews. Drug Discovery·Steven GrantPeter Kirkpatrick
Feb 27, 2007·Cell·Tony Kouzarides
Mar 3, 2007·The Journal of Biological Chemistry·Shwu-Yuan Wu, Cheng-Ming Chiang
Apr 7, 2007·BMC Evolutionary Biology·Torsten H StruckKenneth M Halanych
Aug 19, 2007·Oncogene·S MujtabaM-M Zhou
Nov 7, 2007·Nature Structural & Molecular Biology·Sean D TavernaDinshaw J Patel
Jan 24, 2008·Analytical Biochemistry·Ronald L JohnsonElisabeth D Martinez
Oct 16, 2009·The Journal of Biological Chemistry·Friederike VollmuthMatthias Geyer
Jan 6, 2010·The Journal of Biological Chemistry·Takashi UmeharaShigeyuki Yokoyama
Sep 28, 2010·Nature·Panagis FilippakopoulosJames E Bradner
Nov 12, 2010·Nature·Edwige NicodemeAlexander Tarakhovsky


Sep 22, 2011·Expert Reviews in Molecular Medicine·Susanne MullerStefan Knapp
Dec 6, 2011·Journal of Medicinal Chemistry·Paul BamboroughChun-Wa Chung
Nov 20, 2012·Organic Letters·Yijun HuangAlexander Dömling
Apr 3, 2013·Nature Reviews. Clinical Oncology·Nilofer AzadStephen B Baylin
Aug 23, 2012·Proceedings of the National Academy of Sciences of the United States of America·Hozefa S BandukwalaAnjana Rao
Jan 7, 2014·PloS One·Kevin G McLurePeter R Young
Oct 15, 2014·Nature Reviews. Genetics·Raphaël Rodriguez, Kyle M Miller
Jul 31, 2013·Epigenomics·Melanie R HasslerGerda Egger
Oct 29, 2013·Annual Review of Pharmacology and Toxicology·Lingyan JinGuowei Fang
Nov 20, 2013·Proceedings of the National Academy of Sciences of the United States of America·Sarah PicaudPanagis Filippakopoulos
Apr 10, 2013·Epigenomics·Cassandra L Smith
Dec 18, 2013·Nature Biotechnology·Lars AndersRichard A Young
Apr 23, 2014·Nature Reviews. Drug Discovery·Panagis Filippakopoulos, Stefan Knapp
Feb 12, 2014·Proceedings of the National Academy of Sciences of the United States of America·Gardner S CreechSamuel J Danishefsky
Mar 22, 2014·Future Medicinal Chemistry·John G CummingMichael J Waring
Jan 29, 2014·Future Medicinal Chemistry·Laura E JenningsStuart J Conway
Mar 20, 2013·Nature Chemical Biology·Mark E BunnageLyn H Jones
Jun 23, 2012·Nature Reviews. Cancer·Anna C Belkina, Gerald V Denis
Nov 23, 2013·Expert Opinion on Therapeutic Patents·Jean-Marc GarnierChristopher J Burns
May 30, 2015·Expert Opinion on Drug Discovery·Yu DuBin Hong
Dec 17, 2015·Experimental and Therapeutic Medicine·Yangli SunKunpeng Song
May 4, 2015·Current Opinion in Biotechnology·Gerhard FischerMarko Hyvönen
Dec 29, 2015·Biochemical Pharmacology·Elena FerriCharles E McKenna
Sep 8, 2015·Epigenomics·Wenji YanMingzhou Guo
Nov 10, 2012·Biochemical and Biophysical Research Communications·Olivier GoupilleStany Chrétien
Jan 27, 2012·Trends in Pharmacological Sciences·Rab K PrinjhaKevin Lee
Oct 28, 2011·Current Opinion in Structural Biology·Mark Bycroft
Dec 5, 2014·Genome Medicine·Tania WitteClarissa Gerhauser
Mar 13, 2016·Blood Reviews·Benjamin E PaluchElizabeth A Griffiths
Nov 18, 2015·Journal of Medicinal Chemistry·Frank Anthony RomeroSteven Magnuson
Mar 1, 2016·Expert Opinion on Therapeutic Patents·Anirban GhoshalAjay Kumar Srivastava
Oct 2, 2014·Journal of the Peripheral Nervous System : JPNS·James Inglese
Apr 2, 2014·Biochimica Et Biophysica Acta·Roberto SanchezMing-Ming Zhou
Nov 26, 2015·Epigenomics·Roberta NoberiniTiziana Bonaldi
Jul 6, 2014·Progress in Biophysics and Molecular Biology·Engin CukurogluOzlem Keskin
Aug 1, 2015·Journal of Medicinal Chemistry·Paul BamboroughEmmanuel H Demont
Jul 16, 2015·Pharmaceutical Patent Analyst·Minoru TanakaJames E Bradner
Jun 17, 2015·Epigenomics·Marie JungBernard Haendler
Apr 22, 2014·Chemistry & Biology·Steven G SmithMing-Ming Zhou
Apr 2, 2015·Nature Reviews. Drug Discovery·Jayme L DahlinMichael A Walters
Aug 21, 2012·Cell·Martin M MatzukJames E Bradner
Jul 17, 2014·Drug Discovery Today. Technologies·Dafydd R Owen, John D Trzupek
Feb 22, 2013·Journal of Neurodevelopmental Disorders·Junlin LiXiaocai Gao
Jun 22, 2016·ACS Medicinal Chemistry Letters·Paul BamboroughRobert J Watson
Jul 21, 2016·Clinical Epigenetics·David WeigtGuillaume Médard
Oct 24, 2015·Chemical Reviews·Guangtao ZhangMing-Ming Zhou
Aug 26, 2016·Journal of Medicinal Chemistry·Luca Carlino, Giulio Rastelli
Dec 23, 2016·Journal of Chemical Theory and Computation·Shunzhou WanPeter V Coveney
Feb 24, 2017·Nature Reviews. Cancer·Jake ShorttJames E Bradner
Feb 15, 2017·Journal of Medicinal Chemistry·Zhiqing LiuJia Zhou
Oct 14, 2014·Frontiers in Genetics·Alejandro Cabezas-CruzRaymond J Pierce
May 19, 2017·Nature Communications·Flore MiettonCarlo Petosa
May 14, 2017·Journal of Cellular Physiology·Jonathan T Lloyd, Karen C Glass
Feb 22, 2018·The Journal of Biological Chemistry·Fang HuangB Matija Peterlin
Aug 30, 2017·Physical Chemistry Chemical Physics : PCCP·Chunyan ChengRuibo Wu
Jun 7, 2018·SLAS Discovery·Melanie LeveridgeDarren Green
Feb 19, 2013·Angewandte Chemie·Slava ZieglerHerbert Waldmann
Feb 6, 2014·ChemMedChem·Daniel GallenkampHilmar Weinmann
Oct 12, 2018·Assay and Drug Development Technologies·Pia HanssonHelena Lindmark
Nov 18, 2018·Chemistry : a European Journal·Matthew W Halloran, Jean-Philip Lumb
Apr 14, 2012·Nature Reviews. Drug Discovery·Cheryl H ArrowsmithMatthieu Schapira
Mar 7, 2012·Journal of Biomolecular Screening·Quinn LuSara H Thrall
Aug 22, 2013·Angewandte Chemie·Markus FollmannAlexander Straub
Oct 16, 2013·ChemMedChem·Stefan Knapp, Hilmar Weinmann
Jan 3, 2014·The Journal of Clinical Investigation·Robert M Campbell, Peter J Tummino
Nov 9, 2019·Physical Chemistry Chemical Physics : PCCP·Haiyang ZhongTingjun Hou
Dec 26, 2019·SLAS Discovery·Alexander PhillipouPeter D Craggs
May 20, 2020·SLAS Discovery·Mei DingLovisa Holmberg Schiavone
Oct 1, 2011·Journal of Biomolecular Screening·Chun-Wa Chung, Jason Witherington
Jul 31, 2013·Journal of Biomolecular Screening·Peter R Young
Oct 5, 2019·Nature Structural & Molecular Biology·Roberta Noberini, Tiziana Bonaldi
Oct 9, 2013·Acta Crystallographica. Section D, Biological Crystallography·Graziano Lolli, Roberto Battistutta
Jul 2, 2016·Journal of Physics. Condensed Matter : an Institute of Physics Journal·Sinisa VukovicDavid J Huggins
Nov 25, 2017·MedChemComm·Moses MoustakimPaul E Brennan
Dec 14, 2018·MedChemComm·Yingchao DuanHongmin Liu
Mar 21, 2013·Molecular BioSystems·Yukihiro ItohNaoki Miyata
Jul 18, 2017·Archiv der Pharmazie·Mostafa Radwan, Rabah Serya
Jul 25, 2018·Current Protocols in Pharmacology·Nina I Zolotarjova, Richard Wynn
Nov 14, 2018·Molecular Diversity·Alejandro Speck-Planche, Marcus T Scotti
Aug 7, 2020·Organic & Biomolecular Chemistry·Adam G BondAlessio Ciulli
Jun 1, 2016·Journal of Biosciences·Balasundaram PadmanabhanShailesh Tripathi
Nov 1, 2018·Current Medicinal Chemistry·Victoria Lucia AlonsoEsteban Serra
Jun 3, 2020·The Biochemical Journal·Prashant DeshmukhBalasundaram Padmanabhan
Mar 21, 2013·Clinical Pharmacology and Therapeutics·D C Swinney
Jan 11, 2016·ChemMedChem·Natalie H TheodoulouPhilip G Humphreys
Dec 26, 2017·Expert Review of Precision Medicine and Drug Development·Mohamad M KronfolJoseph L McClay
Dec 4, 2019·Clinical Epigenetics·A GanesanMaría Berdasco
Dec 13, 2017·Journal of Biomolecular Structure & Dynamics·Venkatesan Suryanarayanan, Sanjeev Kumar Singh
Feb 14, 2013·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Zhixiang ChengJialiang Wang
Apr 13, 2018·European Journal of Medicinal Chemistry·Zhiqing LiuJia Zhou

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