title: Disrupting Acetyl-Lysine Recognition: Progress in the Development of Bromodomain Inhibitors.
abstract: Bromodomains, small protein modules that recognize acetylated lysine on histones, play a significant role in the epigenome, where they function as "readers" that ultimately determine the functional outcome of the post-translational modification. Because the initial discovery of selective BET inhibitors have helped define the role of that protein family in oncology and inflammation, BET bromodomains have continued to garner the most attention of any other bromodomain. More recently, non-BET bromodomain inhibitors that are potent and selective have been disclosed for ATAD2, CBP, BRD7/9, BRPF, BRPF/TRIM24, CECR2, SMARCA4, and BAZ2A/B. Such novel inhibitors can be used to probe the physiological function of these non-BET bromodomains and further understanding of their role in certain disease states. Here, we provide an update to the progress in identifying selective bromodomain inhibitors and their use as biological tools, as well as our perspective on the field.
authors.affiliation: Discovery Chemistry, Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: F Anthony
authors.initials: FA
authors.lastname: Romero
authors.affiliation: Constellation Pharmaceuticals, Inc. 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Taylor
authors.affiliation: Discovery Chemistry, Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Terry D
authors.initials: TD
authors.lastname: Crawford
authors.affiliation: Discovery Chemistry, Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Vickie
authors.initials: V
authors.lastname: Tsui
authors.affiliation: Constellation Pharmaceuticals, Inc. 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Côté
authors.affiliation: Discovery Chemistry, Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Steven
authors.initials: S
authors.lastname: Magnuson
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D000107:Acetylation / Q000187:drug effects*; D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D034961:Antigens, Nuclear / Q000378:metabolism; D050882:CREB-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone / Q000037:antagonists & inhibitors / Q000378:metabolism; D004265:DNA Helicases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D055808:Drug Discovery / Q000379:methods; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000378:metabolism*; D008958:Models, Molecular; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology*; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism; D000092468:Bromodomain Containing Proteins
chemical_list: D000074183:ATPases Associated with Diverse Cellular Activities; D048868:Adaptor Proteins, Signal Transducing; D000251:Adenosine Triphosphatases; D034961:Antigens, Nuclear; D050882:CREB-Binding Protein; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D004265:DNA Helicases; D004268:DNA-Binding Proteins; D006657:Histones; D008239:Lysine; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D016601:RNA-Binding Proteins; D054852:Small Molecule Libraries; D014157:Transcription Factors; C436708:BAZ2A protein, human; D000092468:Bromodomain Containing Proteins; C098415:BRD2 protein, human; C109106:BRD3 protein, human; C441289:BRD4 protein, human; C485694:BRD7 protein, human; C587454:BRD9 protein, human; C109570:BRDT protein, human; C086011:BRPF1 protein, human; C576521:Cecr2 protein, human; C555317:TRIM24 protein, human; C406238:fetal Alzheimer antigen; C494363:CREBBP protein, human; C084108:SMARCA4 protein, human; C544857:ATAD2 protein, human