...We Welcome You To The Resverlogix HUB withIn The AGORACOM COMMUNITY!
Message: If anyone still cares about science...
While waiting for a deal to be struck with BP, here are some observations made by researchers from (among others) GlaxoSmithKline - observations on the pharmaceutical benefit of inhibiting BD2 over BD1. Note the comment about "BD2 inhibitors were predominantly effective in models of inflammatory and autoimmune disease".
Inflammation is the keyword. I believe I have said that before. The article was published in Science - it does not really get more prestigious than that. This is what the best researchers in the world believe is the best research.
Science
. 2020 Apr 24;368(6489):387-394.
Selective targeting of BD1 and BD2 of the BET proteins in cancer and immunoinflammation
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 collapse
Affiliations
- 1Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
- 2Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia.
- 3Epigenetics RU, GlaxoSmithKline Medicines Research Centre, Stevenage, UK.
- 4Cellzome GmbH, Functional Genomics R&D, GlaxoSmithKline, Heidelberg, Germany.
- 5Promega Corporation, Madison, WI, USA.
- 6Computational Biology, GlaxoSmithKline, Collegeville, PA, USA.
- 7Centre for Cancer Research, University of Melbourne, Melbourne, VIC, Australia.
- 8Epigenetics RU, GlaxoSmithKline Medicines Research Centre, Stevenage, UK. mark.dawson@petermac.org rabinder.prinjha@gsk.com.
- 9Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. mark.dawson@petermac.org rabinder.prinjha@gsk.com.
#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.
9 Recommendations
Loading...
Loading...
New Message
Please
login
to post a reply