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 YN Lam, Chun-wa Chung, Paul Bamborough, Massimo Petretich, Marjeta Urh, Stephen J Atkinson, Anna K Bassil, Emma J Roberts, Dane Vassiliadis, Marian L Burr, Alex GS Preston, Christopher Wellaway, Thilo Werner, James R Gray Show all
SCIENCE | AMER ASSOC ADVANCEMENT SCIENCE | Published : 2020
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, wh..View full abstract
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Awarded by NHMRC
We thank the following funders for fellowship and grant support: a CCV Dunlop fellowship and an HHMI international research scholarship to M.A.D.; a Victoria Cancer Agency fellowship to O.G. and E.Y. N.L.; CRUK to M.L.B.; and a CSL Centenary fellowship to S.J.D. Work from the Dawson laboratory is supported by grant funding from the NHMRC (1106444, 1144649, 1146192), the University of Melbourne, and the Peter MacCallum Foundation.