title: Promiscuous targeting of bromodomains by bromosporine identifies BET proteins as master regulators of primary transcription response in leukemia.
abstract: Bromodomains (BRDs) have emerged as compelling targets for cancer therapy. The development of selective and potent BET (bromo and extra-terminal) inhibitors and their significant activity in diverse tumor models have rapidly translated into clinical studies and have motivated drug development efforts targeting non-BET BRDs. However, the complex multidomain/subunit architecture of BRD protein complexes complicates predictions of the consequences of their pharmacological targeting. To address this issue, we developed a promiscuous BRD inhibitor [bromosporine (BSP)] that broadly targets BRDs (including BETs) with nanomolar affinity, creating a tool for the identification of cellular processes and diseases where BRDs have a regulatory function. As a proof of principle, we studied the effects of BSP on leukemic cell lines known to be sensitive to BET inhibition and found, as expected, strong antiproliferative activity. Comparison of the modulation of transcriptional profiles by BSP after a short exposure to the inhibitor resulted in a BET inhibitor signature but no significant additional changes in transcription that could account for inhibition of other BRDs. Thus, nonselective targeting of BRDs identified BETs, but not other BRDs, as master regulators of context-dependent primary transcription response.
authors.affiliation: Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, U.K.
authors.forename: Sarah
authors.initials: S
authors.lastname: Picaud
authors.affiliation: Laboratory of Childhood Leukemia, Department of Biomedicine, University of Basel and Basel University Children's Hospital, Hebelstrasse 20, CH-4031 Basel, Switzerland.
authors.forename: Katharina
authors.initials: K
authors.lastname: Leonards
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Lambert
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, U.K.
authors.forename: Oliver
authors.initials: O
authors.lastname: Dovey
authors.affiliation: Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, U.K.
authors.forename: Christopher
authors.identifier: 0000-0001-9985-9816
authors.initials: C
authors.lastname: Wells
authors.affiliation: Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, U.K.; Target Discovery Institute, University of Oxford, Oxford OX3 7FZ, U.K.
authors.forename: Oleg
authors.identifier: 0000-0002-8662-7300
authors.initials: O
authors.lastname: Fedorov
authors.affiliation: Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, U.K.; Target Discovery Institute, University of Oxford, Oxford OX3 7FZ, U.K.
authors.forename: Octovia
authors.initials: O
authors.lastname: Monteiro
authors.affiliation: Ludwig Institute for Cancer Research, University of Oxford, Oxford OX3 7DQ, U.K.
authors.forename: Takao
authors.initials: T
authors.lastname: Fujisawa
authors.affiliation: Ludwig Institute for Cancer Research, University of Oxford, Oxford OX3 7DQ, U.K.
authors.forename: Chen-Yi
authors.initials: CY
authors.lastname: Wang
authors.affiliation: Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, U.K.
authors.forename: Hannah
authors.initials: H
authors.lastname: Lingard
authors.affiliation: Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, U.K.; Target Discovery Institute, University of Oxford, Oxford OX3 7FZ, U.K.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Tallant
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, U.K.
authors.forename: Nikzad
authors.identifier: 0000-0002-2268-4090
authors.initials: N
authors.lastname: Nikbin
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, U.K.
authors.forename: Lucie
authors.initials: L
authors.lastname: Guetzoyan
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, U.K.
authors.forename: Richard
authors.identifier: 0000-0003-2463-3323
authors.initials: R
authors.lastname: Ingham
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, U.K.
authors.forename: Steven V
authors.initials: SV
authors.lastname: Ley
authors.affiliation: Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, U.K.; Target Discovery Institute, University of Oxford, Oxford OX3 7FZ, U.K.; Alzheimer's Research UK Oxford, Nuffield Department of Medicine Research Building, University of Oxford, Oxford OX3 7FZ, U.K.
authors.forename: Paul
authors.identifier: 0000-0002-8950-7646
authors.initials: P
authors.lastname: Brennan
authors.affiliation: Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, U.K.; Target Discovery Institute, University of Oxford, Oxford OX3 7FZ, U.K.
authors.forename: Susanne
authors.identifier: 0000-0003-2402-4157
authors.initials: S
authors.lastname: Muller
authors.affiliation: Department of Oncology, CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford OX3 7DQ, U.K.
authors.forename: Anastasia
authors.identifier: 0000-0002-9353-9173
authors.initials: A
authors.lastname: Samsonova
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada.; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Anne-Claude
authors.identifier: 0000-0002-6090-4437
authors.initials: AC
authors.lastname: Gingras
authors.affiliation: Laboratory of Childhood Leukemia, Department of Biomedicine, University of Basel and Basel University Children's Hospital, Hebelstrasse 20, CH-4031 Basel, Switzerland.
authors.forename: Juerg
authors.initials: J
authors.lastname: Schwaller
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, U.K.; Department of Haematology, Cambridge University Hospitals NHS Trust, Cambridge CB2 0QQ, U.K.; Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0XY, U.K.
authors.forename: George
authors.identifier: 0000-0003-4337-8022
authors.initials: G
authors.lastname: Vassiliou
authors.affiliation: Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, U.K.; Target Discovery Institute, University of Oxford, Oxford OX3 7FZ, U.K.; Institute for Pharmaceutical Chemistry and Buchmann Institute for Life Sciences, Goethe University, Max-von Laue Str. 9, 60438 Frankfurt am Main, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Knapp
authors.affiliation: Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, U.K.; Ludwig Institute for Cancer Research, University of Oxford, Oxford OX3 7DQ, U.K.
authors.forename: Panagis
authors.identifier: 0000-0002-1515-1317
authors.initials: P
authors.lastname: Filippakopoulos
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D016503:Drug Delivery Systems; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D057809:HEK293 Cells; D006801:Humans; D020014:K562 Cells; D007938:Leukemia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D014157:Transcription Factors
keywords: BET; Bromodomains; epigenetics; inhibition; leukemias