1. Selective targeting of BD1 and BD2 of the BET proteins in cancer and immunoinflammation.
- Author
-
Gilan O, Rioja I, Knezevic K, Bell MJ, Yeung MM, Harker NR, Lam EYN, Chung CW, Bamborough P, Petretich M, Urh M, Atkinson SJ, Bassil AK, Roberts EJ, Vassiliadis D, Burr ML, Preston AGS, Wellaway C, Werner T, Gray JR, Michon AM, Gobbetti T, Kumar V, Soden PE, Haynes A, Vappiani J, Tough DF, Taylor S, Dawson SJ, Bantscheff M, Lindon M, Drewes G, Demont EH, Daniels DL, Grandi P, Prinjha RK, and Dawson MA
- Subjects
- Anti-Inflammatory Agents, Non-Steroidal chemistry, Anti-Inflammatory Agents, Non-Steroidal therapeutic use, Antineoplastic Agents therapeutic use, Cell Cycle Proteins chemistry, Cell Cycle Proteins genetics, Drug Discovery, Gene Expression Regulation, Neoplastic drug effects, HEK293 Cells, Histone Acetyltransferases chemistry, Histone Acetyltransferases genetics, Humans, Immune System Diseases drug therapy, Immunologic Factors chemistry, Immunologic Factors therapeutic use, Inflammation drug therapy, Neoplasms drug therapy, Protein Domains drug effects, Transcription Factors chemistry, Transcription Factors genetics, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Antineoplastic Agents pharmacology, Cell Cycle Proteins antagonists & inhibitors, Histone Acetyltransferases antagonists & inhibitors, Immunologic Factors pharmacology, Molecular Targeted Therapy, Transcription Factors antagonists & inhibitors
- 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., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
- Published
- 2020
- Full Text
- View/download PDF