Selective targeting of BD1 and BD2 of the BET proteins in cancer and immunoinflammation.
Anti-Inflammatory Agents, Non-Steroidal
/ chemistry
Antineoplastic Agents
/ pharmacology
Cell Cycle Proteins
/ antagonists & inhibitors
Drug Discovery
Gene Expression Regulation, Neoplastic
/ drug effects
HEK293 Cells
Histone Acetyltransferases
/ antagonists & inhibitors
Humans
Immune System Diseases
/ drug therapy
Immunologic Factors
/ chemistry
Inflammation
/ drug therapy
Molecular Targeted Therapy
Neoplasms
/ drug therapy
Protein Domains
/ drug effects
Transcription Factors
/ antagonists & inhibitors
Journal
Science (New York, N.Y.)
ISSN: 1095-9203
Titre abrégé: Science
Pays: United States
ID NLM: 0404511
Informations de publication
Date de publication:
24 04 2020
24 04 2020
Historique:
received:
23
10
2019
accepted:
06
03
2020
pubmed:
21
3
2020
medline:
15
5
2020
entrez:
21
3
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32193360
pii: science.aaz8455
doi: 10.1126/science.aaz8455
pmc: PMC7610820
mid: EMS123766
doi:
Substances chimiques
Anti-Inflammatory Agents, Non-Steroidal
0
Antineoplastic Agents
0
BRD3 protein, human
0
BRD4 protein, human
0
Cell Cycle Proteins
0
Immunologic Factors
0
Transcription Factors
0
BRD1 protein, human
EC 2.3.1.48
Histone Acetyltransferases
EC 2.3.1.48
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
387-394Subventions
Organisme : Cancer Research UK
ID : A20097
Pays : United Kingdom
Commentaires et corrections
Type : CommentIn
Type : CommentIn
Type : CommentIn
Informations de copyright
Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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