دورية أكاديمية
Targeting the NFAT:AP-1 transcriptional complex on DNA with a small-molecule inhibitor.
العنوان: | Targeting the NFAT:AP-1 transcriptional complex on DNA with a small-molecule inhibitor. |
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المؤلفون: | Mognol GP; Division of Signaling and Gene Expression, La Jolla Institute for Immunology, La Jolla, CA 92037., González-Avalos E; Division of Signaling and Gene Expression, La Jolla Institute for Immunology, La Jolla, CA 92037.; Bioinformatics and Systems Biology Graduate Program, University of California, San Diego, La Jolla, CA 92093., Ghosh S; Immune Disease Institute, Boston Children's Hospital, Boston, MA 02115.; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115., Spreafico R; Signaling Systems Laboratory, University of California, Los Angeles, CA 90095., Gudlur A; Division of Signaling and Gene Expression, La Jolla Institute for Immunology, La Jolla, CA 92037., Rao A; Division of Signaling and Gene Expression, La Jolla Institute for Immunology, La Jolla, CA 92037.; Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037.; Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093.; Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093., Damoiseaux R; Molecular Screening Shared Resource, California NanoSystems Institute, University of California, Los Angeles, CA 90095., Hogan PG; Division of Signaling and Gene Expression, La Jolla Institute for Immunology, La Jolla, CA 92037; phogan@lji.org.; Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093.; Program in Immunology, University of California, San Diego, La Jolla, CA 92037. |
المصدر: | Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2019 May 14; Vol. 116 (20), pp. 9959-9968. Date of Electronic Publication: 2019 Apr 24. |
نوع المنشور: | Evaluation Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
اللغة: | English |
بيانات الدورية: | Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1091-6490 (Electronic) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE |
أسماء مطبوعة: | Original Publication: Washington, DC : National Academy of Sciences |
مواضيع طبية MeSH: | Acetamides/*pharmacology , Gene Expression/*drug effects , NFATC Transcription Factors/*antagonists & inhibitors , Transcription Factor AP-1/*antagonists & inhibitors, Cytokines/metabolism ; DNA/metabolism ; Escherichia coli ; High-Throughput Screening Assays ; NFATC Transcription Factors/metabolism ; Proof of Concept Study ; Small Molecule Libraries ; Transcription Factor AP-1/metabolism |
مستخلص: | 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, N -(3-acetamidophenyl)-2-[5-(1H-benzimidazol-2-yl)pyridin-2-yl]sulfanylacetamide (Compound 10), which disrupts the NFAT:AP-1 interaction at the composite antigen-receptor response element-2 site without affecting the binding of NFAT or AP-1 alone to DNA. Compound 10 binds to DNA in a sequence-selective manner and inhibits the transcription of the Il2 gene and several other cyclosporin A-sensitive cytokine genes important for the effector immune response. This study provides proof-of-concept that small molecules can inhibit the assembly of specific DNA-protein complexes, and opens a potential new approach to treat human diseases where known transcription factors are deregulated. Competing Interests: 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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معلومات مُعتمدة: | S10 OD016262 United States OD NIH HHS; R01 AI040127 United States AI NIAID NIH HHS; R01 AI109842 United States AI NIAID NIH HHS; S10 RR027366 United States RR NCRR NIH HHS; R56 AI109842 United States AI NIAID NIH HHS; P30 CA016042 United States CA NCI NIH HHS |
فهرسة مساهمة: | Keywords: FRET assay; Fos; Jun; NFAT; cyclosporin A |
المشرفين على المادة: | 0 (Acetamides) 0 (Cytokines) 0 (NFATC Transcription Factors) 0 (Small Molecule Libraries) 0 (Transcription Factor AP-1) 9007-49-2 (DNA) |
تواريخ الأحداث: | Date Created: 20190426 Date Completed: 20200330 Latest Revision: 20200330 |
رمز التحديث: | 20231215 |
مُعرف محوري في PubMed: | PMC6525529 |
DOI: | 10.1073/pnas.1820604116 |
PMID: | 31019078 |
قاعدة البيانات: | MEDLINE |
تدمد: | 1091-6490 |
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DOI: | 10.1073/pnas.1820604116 |