2. Academic Validation
  3. Selective targeting of BD1 and BD2 of the BET proteins in cancer and immunoinflammation

Selective targeting of BD1 and BD2 of the BET proteins in cancer and immunoinflammation

  • Science. 2020 Apr 24;368(6489):387-394. doi: 10.1126/science.aaz8455.
Omer Gilan  # 1 2,  Inmaculada Rioja  # 3,  Kathy Knezevic 1,  Matthew J Bell 3,  Miriam M Yeung 1,  Nicola R Harker 3,  Enid Y N Lam 1 2,  Chun-Wa Chung 3,  Paul Bamborough 3,  Massimo Petretich 4,  Marjeta Urh 5,  Stephen J Atkinson 3,  Anna K Bassil 3,  Emma J Roberts 3,  Dane Vassiliadis 1 2,  Marian L Burr 1 2,  Alex G S Preston 3,  Christopher Wellaway 3,  Thilo Werner 4,  James R Gray 3,  Anne-Marie Michon 4,  Thomas Gobbetti 3,  Vinod Kumar 6,  Peter E Soden 3,  Andrea Haynes 3,  Johanna Vappiani 4,  David F Tough 3,  Simon Taylor 3,  Sarah-Jane Dawson 1 2 7,  Marcus Bantscheff 4,  Matthew Lindon 3,  Gerard Drewes 4,  Emmanuel H Demont 3,  Danette L Daniels 5,  Paola Grandi 4,  Rab K Prinjha  # 8,  Mark A Dawson  # 9 2 7
Affiliations

Affiliations

  • 1 Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
  • 2 Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia.
  • 3 Epigenetics RU, GlaxoSmithKline Medicines Research Centre, Stevenage, UK.
  • 4 Cellzome GmbH, Functional Genomics R&D, GlaxoSmithKline, Heidelberg, Germany.
  • 5 Promega Corporation, Madison, WI, USA.
  • 6 Computational Biology, GlaxoSmithKline, Collegeville, PA, USA.
  • 7 Centre for Cancer Research, University of Melbourne, Melbourne, VIC, Australia.
  • 8 Epigenetics RU, GlaxoSmithKline Medicines Research Centre, Stevenage, UK. [email protected] [email protected].
  • 9 Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. [email protected] [email protected].
  • # Contributed equally.
PMID: 32193360 DOI: 10.1126/science.aaz8455
Abstract

The two tandem bromodomains of the BET (bromodomain and extraterminal domain) proteins enable chromatin binding to facilitate transcription. Drugs that inhibit both bromodomains equally have shown efficacy in certain malignant and inflammatory conditions. To explore the individual functional contributions of the first (BD1) and second (BD2) bromodomains in biology and therapy, we developed selective BD1 and BD2 inhibitors. We found that steady-state gene expression primarily requires BD1, whereas the rapid increase of gene expression induced by inflammatory stimuli requires both BD1 and BD2 of all BET proteins. BD1 inhibitors phenocopied the effects of pan-BET inhibitors in Cancer models, whereas BD2 inhibitors were predominantly effective in models of inflammatory and autoimmune disease. These insights into the differential requirement of BD1 and BD2 for the maintenance and induction of gene expression may guide future BET-targeted therapies.

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