دورية أكاديمية
أعرض في EDS

Targeting the NFAT:AP-1 transcriptional complex on DNA with a small-molecule inhibitor.

التفاصيل البيبلوغرافية
العنوان: Targeting the NFAT:AP-1 transcriptional complex on DNA with a small-molecule inhibitor.
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.
References: Science. 1999 Sep 24;285(5436):2129-33. (PMID: 10497131)
J Biomol Screen. 1999;4(2):67-73. (PMID: 10838414)
Oncogene. 2000 Jun 1;19(24):2820-7. (PMID: 10851085)
J Immunol. 2000 Jul 1;165(1):297-305. (PMID: 10861065)
EMBO J. 2000 Sep 1;19(17):4783-95. (PMID: 10970869)
Mol Cell. 2000 Sep;6(3):539-50. (PMID: 11030334)
Immunol Today. 2000 Nov;21(11):567-73. (PMID: 11094261)
J Exp Med. 2001 Mar 5;193(5):607-20. (PMID: 11238591)
Oncogene. 2001 Apr 30;20(19):2476-89. (PMID: 11402342)
Nat Immunol. 2002 Jul;3(7):643-51. (PMID: 12055628)
Nat Cell Biol. 2002 Jul;4(7):540-4. (PMID: 12080349)
Cell. 2002 Jun 14;109(6):719-31. (PMID: 12086671)
Immunity. 2002 Jun;16(6):881-95. (PMID: 12121669)
Curr Opin Struct Biol. 2003 Jun;13(3):284-99. (PMID: 12831879)
Genes Dev. 2003 Sep 15;17(18):2205-32. (PMID: 12975316)
Nat Med. 2004 Mar;10(3):305-9. (PMID: 14770176)
Proc Natl Acad Sci U S A. 2004 May 18;101(20):7554-9. (PMID: 15131267)
Eukaryot Cell. 2004 Jun;3(3):695-704. (PMID: 15189990)
J Mol Biol. 2004 Oct 1;342(5):1659-74. (PMID: 15364589)
Nat Rev Immunol. 2005 Jun;5(6):472-84. (PMID: 15928679)
J Biol Chem. 2005 Oct 21;280(42):35209-16. (PMID: 16109714)
J Immunol. 1992 Feb 15;148(4):1240-50. (PMID: 1737937)
J Mol Biol. 2007 Jun 22;369(5):1296-306. (PMID: 17498738)
Immunity. 2007 Oct;27(4):670-84. (PMID: 17950003)
Nat Immunol. 2008 Apr;9(4):432-43. (PMID: 18327260)
Nat Methods. 2009 Aug;6(8):569-75. (PMID: 19644458)
J Exp Med. 1991 Mar 1;173(3):619-28. (PMID: 1997649)
Trends Cell Biol. 2011 Feb;21(2):91-103. (PMID: 21115349)
ACS Comb Sci. 2011 Sep 12;13(5):537-46. (PMID: 21848276)
Nat Protoc. 2014 Jan;9(1):171-81. (PMID: 24385147)
Nucleic Acids Res. 1988 Mar 25;16(6):2671-90. (PMID: 2452403)
J Med Chem. 2014 Sep 25;57(18):7792-7. (PMID: 25162754)
J Immunol. 2016 Mar 1;196(5):2015-9. (PMID: 26851216)
Cell Death Dis. 2016 Apr 21;7:e2199. (PMID: 27100893)
Proc Natl Acad Sci U S A. 2017 Mar 28;114(13):E2776-E2785. (PMID: 28283662)
J Leukoc Biol. 2017 Sep;102(3):601-615. (PMID: 28606939)
Bioorg Med Chem. 2018 May 1;26(8):1393-1411. (PMID: 29439914)
Beilstein J Org Chem. 2018 May 16;14:1051-1086. (PMID: 29977379)
Proc Natl Acad Sci U S A. 1995 Nov 7;92(23):10506-10. (PMID: 7479829)
Proc Natl Acad Sci U S A. 1995 Nov 21;92(24):11205-9. (PMID: 7479966)
J Biol Chem. 1995 Feb 24;270(8):4138-45. (PMID: 7876165)
Mol Cell Biol. 1995 Apr;15(4):2071-9. (PMID: 7891702)
Proc Natl Acad Sci U S A. 1994 Sep 27;91(20):9203-7. (PMID: 7937742)
J Biol Chem. 1994 Dec 2;269(48):30445-50. (PMID: 7982959)
J Immunol. 1993 Jul 15;151(2):837-48. (PMID: 8335913)
J Exp Med. 1993 Oct 1;178(4):1365-79. (PMID: 8376940)
Nature. 1993 Sep 23;365(6444):352-5. (PMID: 8397339)
Science. 1996 Mar 1;271(5253):1272-6. (PMID: 8638107)
Proc Natl Acad Sci U S A. 1996 Nov 26;93(24):13671-6. (PMID: 8942992)
Annu Rev Immunol. 1997;15:707-47. (PMID: 9143705)
Nature. 1998 Mar 5;392(6671):42-8. (PMID: 9510247)
Proc Natl Acad Sci U S A. 1998 Jul 7;95(14):7915-20. (PMID: 9653115)
Mol Cell. 1998 Apr;1(5):627-37. (PMID: 9660947)
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
الوصف
تدمد:1091-6490
DOI:10.1073/pnas.1820604116