Back
Full-text
Journal article

Promiscuous targeting of bromodomains by bromosporine identifies BET proteins as master regulators of primary transcription response in leukemia.

  • Picaud S Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, U.K.
  • Leonards K Laboratory of Childhood Leukemia, Department of Biomedicine, University of Basel and Basel University Children's Hospital, Hebelstrasse 20, CH-4031 Basel, Switzerland.
  • Lambert JP Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada.
  • Dovey O Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, U.K.
  • Wells C Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, U.K.
  • Fedorov O 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.
  • Monteiro O 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.
  • Fujisawa T Ludwig Institute for Cancer Research, University of Oxford, Oxford OX3 7DQ, U.K.
  • Wang CY Ludwig Institute for Cancer Research, University of Oxford, Oxford OX3 7DQ, U.K.
  • Lingard H Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, U.K.
  • Tallant C 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.
  • Nikbin N Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, U.K.
  • Guetzoyan L Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, U.K.
  • Ingham R Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, U.K.
  • Ley SV Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, U.K.
  • Brennan P 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.
  • Muller S 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.
  • Samsonova A Department of Oncology, CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford OX3 7DQ, U.K.
  • Gingras AC Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada.; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
  • Schwaller J Laboratory of Childhood Leukemia, Department of Biomedicine, University of Basel and Basel University Children's Hospital, Hebelstrasse 20, CH-4031 Basel, Switzerland.
  • Vassiliou G 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.
  • Knapp S 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.
  • Filippakopoulos P 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.
Show more…
  • 2016-10-21
Published in:
  • Science advances. - 2016
BET
Bromodomains
epigenetics
inhibition
leukemias
Antineoplastic Agents
Drug Delivery Systems
Gene Expression Regulation, Leukemic
HEK293 Cells
Humans
K562 Cells
Leukemia
Neoplasm Proteins
Transcription Factors
Transcription, Genetic
English 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.
Language
  • English
Open access status
gold
Identifiers
Persistent URL
https://sonar.ch/global/documents/91993
Statistics
Document views: 28 File downloads:
  • fulltext.pdf: 0