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

Omer Gilan, Inmaculada Rioja, Kathy Knezevic, Matthew J. Bell, Miriam M. Yeung, Nicola R. Harker, Enid Y.N. Lam, Chunwa Chung, Paul Bamborough, Massimo Petretich, Marjeta Urh, Stephen J. Atkinson, Anna K. Bassil, Emma J. Roberts, Dane Vassiliadis, Marian L. Burr, Alex G.S. Preston, Christopher Wellaway, Thilo Werner, James R. GrayAnne Marie Michon, Thomas Gobbetti, Vinod Kumar, Peter E. Soden, Andrea Haynes, Johanna Vappiani, David F. Tough, Simon Taylor, Sarah-Jane Dawson, Marcus Bantscheff, Matthew Lindon, Gerard Drewes, Emmanuel H. Demont, Danette L. Daniels, Paola Grandi, Rab K. Prinjha, Mark A. Dawson

Research output: Contribution to journalArticleResearchpeer-review

246 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)387-394
Number of pages8
Issue number6489
Publication statusPublished - 24 Apr 2020
Externally publishedYes

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