Targeting the NFAT:AP-1 transcriptional complex on DNA with a small-molecule inhibitor.
Acetamides
/ pharmacology
Cytokines
/ metabolism
DNA
/ metabolism
Escherichia coli
Gene Expression
/ drug effects
High-Throughput Screening Assays
NFATC Transcription Factors
/ antagonists & inhibitors
Proof of Concept Study
Small Molecule Libraries
Transcription Factor AP-1
/ antagonists & inhibitors
FRET assay
Fos
Jun
NFAT
cyclosporin A
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
14 05 2019
14 05 2019
Historique:
pubmed:
26
4
2019
medline:
31
3
2020
entrez:
26
4
2019
Statut:
ppublish
Résumé
The transcription factor nuclear factor of activated T cells (NFAT) has a key role in both T cell activation and tolerance and has emerged as an important target of immune modulation. NFAT directs the effector arm of the immune response in the presence of activator protein-1 (AP-1), and T cell anergy/exhaustion in the absence of AP-1. Envisioning a strategy for selective modulation of the immune response, we designed a FRET-based high-throughput screen to identify compounds that disrupt the NFAT:AP-1:DNA complex. We screened ∼202,000 small organic compounds and identified 337 candidate inhibitors. We focus here on one compound,
Identifiants
pubmed: 31019078
pii: 1820604116
doi: 10.1073/pnas.1820604116
pmc: PMC6525529
doi:
Substances chimiques
Acetamides
0
Cytokines
0
NFATC Transcription Factors
0
Small Molecule Libraries
0
Transcription Factor AP-1
0
DNA
9007-49-2
Types de publication
Evaluation Study
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
9959-9968Subventions
Organisme : NIH HHS
ID : S10 OD016262
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI040127
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI109842
Pays : United States
Organisme : NCRR NIH HHS
ID : S10 RR027366
Pays : United States
Organisme : NIAID NIH HHS
ID : R56 AI109842
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA016042
Pays : United States
Déclaration de conflit d'intérêts
Conflict of interest statement: A.R. and P.G.H. are founders of CalciMedica, Inc., and members of its scientific advisory board.
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