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

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

Science (American Association for the Advancement of Science), 2020-04, Vol.368 (6489), p.387-394 [Periódico revisado por pares]

United States: The American Association for the Advancement of Science

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Título:
Selective targeting of BD1 and BD2 of the BET proteins in cancer and immunoinflammation
Autor: Gilan, Omer ; Rioja, Inmaculada ; Knezevic, Kathy ; Bell, Matthew J ; Yeung, Miriam M ; Harker, Nicola R ; Lam, Enid Y N ; Chung, Chun-Wa ; Bamborough, Paul ; Petretich, Massimo ; Urh, Marjeta ; Atkinson, Stephen J ; Bassil, Anna K ; Roberts, Emma J ; Vassiliadis, Dane ; Burr, Marian L ; Preston, Alex G S ; Wellaway, Christopher ; Werner, Thilo ; Gray, James R ; Michon, Anne-Marie ; Gobbetti, Thomas ; Kumar, Vinod ; Soden, Peter E ; Haynes, Andrea ; Vappiani, Johanna ; Tough, David F ; Taylor, Simon ; Dawson, Sarah-Jane ; Bantscheff, Marcus ; Lindon, Matthew ; Drewes, Gerard ; Demont, Emmanuel H ; Daniels, Danette L ; Grandi, Paola ; Prinjha, Rab K ; Dawson, Mark A
Assuntos: Anti-Inflammatory Agents, Non-Steroidal - chemistry ; Anti-Inflammatory Agents, Non-Steroidal - pharmacology ; Anti-Inflammatory Agents, Non-Steroidal - therapeutic use ; Antineoplastic Agents - pharmacology ; Antineoplastic Agents - therapeutic use ; Autoimmune diseases ; Cancer ; Cell Cycle Proteins - antagonists & inhibitors ; Cell Cycle Proteins - chemistry ; Cell Cycle Proteins - genetics ; Chromatin ; Clinical trials ; Drug development ; Drug Discovery ; Drugs ; Gene expression ; Gene Expression Regulation, Neoplastic - drug effects ; Gene regulation ; HEK293 Cells ; Histone Acetyltransferases - antagonists & inhibitors ; Histone Acetyltransferases - chemistry ; Histone Acetyltransferases - genetics ; Humans ; Immune System Diseases - drug therapy ; Immunologic Factors - chemistry ; Immunologic Factors - pharmacology ; Immunologic Factors - therapeutic use ; Immunological diseases ; Immunosuppressive agents ; Inflammation - drug therapy ; Inhibitors ; Molecular Targeted Therapy ; Narcotics ; Neoplasms - drug therapy ; Pathogenesis ; Protein Domains - drug effects ; Proteins ; Transcription ; Transcription Factors - antagonists & inhibitors ; Transcription Factors - chemistry ; Transcription Factors - genetics
É parte de: Science (American Association for the Advancement of Science), 2020-04, Vol.368 (6489), p.387-394
Descrição: 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.
Editor: United States: The American Association for the Advancement of Science
Idioma: Inglês

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

United States: The American Association for the Advancement of Science

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