title: New Synthetic Routes to Triazolo-benzodiazepine Analogues: Expanding the Scope of the Bump-and-Hole Approach for Selective Bromo and Extra-Terminal (BET) Bromodomain Inhibition.
abstract: We describe new synthetic routes developed toward a range of substituted analogues of bromo and extra-terminal (BET) bromodomain inhibitors I-BET762/JQ1 based on the triazolo-benzodiazepine scaffold. These new routes allow for the derivatization of the methoxyphenyl and chlorophenyl rings, in addition to the diazepine ternary center and the side chain methylene moiety. Substitution at the level of the side chain methylene afforded compounds targeting specifically and potently engineered BET bromodomains designed as part of a bump and hole approach. We further demonstrate that marked selectivity for the second over the first bromodomain can be achieved with an indole derivative that exploits differential interaction with an aspartate/histidine conservative substitution on the BC loop of BET bromodomains.
authors.affiliation: Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee , James Black Centre, Dow Street, Dundee DD1 5EH, U.K.|Department of Chemistry, University of Cambridge , Lensfield Road, Cambridge CB2 1EW, U.K.
authors.forename: Matthias G J
authors.initials: MG
authors.lastname: Baud
authors.affiliation: Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee , James Black Centre, Dow Street, Dundee DD1 5EH, U.K.|Department of Chemistry, University of Cambridge , Lensfield Road, Cambridge CB2 1EW, U.K.
authors.forename: Enrique
authors.initials: E
authors.lastname: Lin-Shiao
authors.affiliation: Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee , James Black Centre, Dow Street, Dundee DD1 5EH, U.K.
authors.forename: Michael
authors.initials: M
authors.lastname: Zengerle
authors.affiliation: Department of Chemistry, University of Cambridge , Lensfield Road, Cambridge CB2 1EW, U.K.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Tallant
authors.affiliation: Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee , James Black Centre, Dow Street, Dundee DD1 5EH, U.K.|Department of Chemistry, University of Cambridge , Lensfield Road, Cambridge CB2 1EW, U.K.
authors.forename: Alessio
authors.initials: A
authors.lastname: Ciulli
mesh_terms: D001569:Benzodiazepines / Q000737:chemistry* / Q000494:pharmacology*; D018797:Cell Cycle Proteins; D015195:Drug Design; D006801:Humans; D062105:Molecular Docking Simulation; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D014230:Triazoles / Q000737:chemistry* / Q000494:pharmacology*; D000092468:Bromodomain Containing Proteins
chemical_list: D001569:Benzodiazepines; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D014157:Transcription Factors; D014230:Triazoles; C098415:BRD2 protein, human; D000092468:Bromodomain Containing Proteins; C441289:BRD4 protein, human; C554645:molibresib