title: Discovery and characterization of small molecule inhibitors of the BET family bromodomains.
abstract: 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.
authors.affiliation: Molecular Discovery Research, GlaxoSmithKline R&D, Stevenage SG5 4HT, UK. Chun-Wa.H.Chung@gsk.com
authors.forename: Chun-Wa
authors.initials: CW
authors.lastname: Chung
authors.forename: Herve
authors.initials: H
authors.lastname: Coste
authors.forename: Julia H
authors.initials: JH
authors.lastname: White
authors.forename: Olivier
authors.initials: O
authors.lastname: Mirguet
authors.forename: Jonathan
authors.initials: J
authors.lastname: Wilde
authors.forename: Romain L
authors.initials: RL
authors.lastname: Gosmini
authors.forename: Chris
authors.initials: C
authors.lastname: Delves
authors.forename: Sylvie M
authors.initials: SM
authors.lastname: Magny
authors.forename: Robert
authors.initials: R
authors.lastname: Woodward
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Hughes
authors.forename: Eric V
authors.initials: EV
authors.lastname: Boursier
authors.forename: Helen
authors.initials: H
authors.lastname: Flynn
authors.forename: Anne M
authors.initials: AM
authors.lastname: Bouillot
authors.forename: Paul
authors.initials: P
authors.lastname: Bamborough
authors.forename: Jean-Marie G
authors.initials: JM
authors.lastname: Brusq
authors.forename: Francoise J
authors.initials: FJ
authors.lastname: Gellibert
authors.forename: Emma J
authors.initials: EJ
authors.lastname: Jones
authors.forename: Alizon M
authors.initials: AM
authors.lastname: Riou
authors.forename: Paul
authors.initials: P
authors.lastname: Homes
authors.forename: Sandrine L
authors.initials: SL
authors.lastname: Martin
authors.forename: Iain J
authors.initials: IJ
authors.lastname: Uings
authors.forename: Jerome
authors.initials: J
authors.lastname: Toum
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Clement
authors.forename: Anne-Benedicte
authors.initials: AB
authors.lastname: Boullay
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Grimley
authors.forename: Florence M
authors.initials: FM
authors.lastname: Blandel
authors.forename: Rab K
authors.initials: RK
authors.lastname: Prinjha
authors.forename: Kevin
authors.initials: K
authors.lastname: Lee
authors.forename: Jorge
authors.initials: J
authors.lastname: Kirilovsky
authors.forename: Edwige
authors.initials: E
authors.lastname: Nicodeme
mesh_terms: D000107:Acetylation; D000595:Amino Acid Sequence; D016632:Apolipoprotein A-I / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D001569:Benzodiazepines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D057890:Epigenomics; D056945:Hep G2 Cells; D006657:Histones / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D058990:Molecular Targeted Therapy; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D013237:Stereoisomerism; D014157:Transcription Factors; D015854:Up-Regulation; D000092468:Bromodomain Containing Proteins
chemical_list: D016632:Apolipoprotein A-I; D001569:Benzodiazepines; D006657:Histones; D008239:Lysine; D017346:Protein Serine-Threonine Kinases; D014157:Transcription Factors; C505693:APOA1 protein, human; C098415:BRD2 protein, human; D000092468:Bromodomain Containing Proteins