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

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

  • Proc Natl Acad Sci U S A. 2019 May 14;116(20):9959-9968. doi: 10.1073/pnas.1820604116.
Giuliana P Mognol 1,  Edahí González-Avalos 1 2,  Srimoyee Ghosh 3 4,  Roberto Spreafico 5,  Aparna Gudlur 1,  Anjana Rao 1 6 7 8,  Robert Damoiseaux 9,  Patrick G Hogan 10 8 11
Affiliations

Affiliations

  • 1 Division of Signaling and Gene Expression, La Jolla Institute for Immunology, La Jolla, CA 92037.
  • 2 Bioinformatics and Systems Biology Graduate Program, University of California, San Diego, La Jolla, CA 92093.
  • 3 Immune Disease Institute, Boston Children's Hospital, Boston, MA 02115.
  • 4 Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115.
  • 5 Signaling Systems Laboratory, University of California, Los Angeles, CA 90095.
  • 6 Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037.
  • 7 Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093.
  • 8 Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093.
  • 9 Molecular Screening Shared Resource, California NanoSystems Institute, University of California, Los Angeles, CA 90095.
  • 10 Division of Signaling and Gene Expression, La Jolla Institute for Immunology, La Jolla, CA 92037; phogan@lji.org.
  • 11 Program in Immunology, University of California, San Diego, La Jolla, CA 92037.
PMID: 31019078 DOI: 10.1073/pnas.1820604116
Abstract

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.

Keywords

FRET assay; Fos; Jun; NFAT; cyclosporin A.

Figures
Products