Journal article

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

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, wh..

View full abstract