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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE125446 | GEO | 2019/01/23

REPOSITORIES: GEO

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

Project description: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.

| S-EPMC6525529 | biostudies-literature

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

Project description:The transcription factor 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 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 ARRE-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 CsA-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.

2019-01-23 | GSE125445 | GEO

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

2019-01-23 | GSE125444 | GEO

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

2019-01-23 | GSE125443 | GEO

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

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

| PRJNA516414 | ENA

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

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

| PRJNA516418 | ENA

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

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

| PRJNA516417 | ENA

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

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

| PRJNA516419 | ENA

Targeting of the NOTCH transcription complex by a novel small molecule inhibitor CB-103

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-12-19 | GSE142408 | GEO

Small molecule inhibitors targeting activator protein 1 (AP-1).

Project description:Activator protein 1 (AP-1) is a pivotal transcription factor that regulates a wide range of cellular processes including proliferation, apoptosis, differentiation, survival, cell migration, and transformation. Accumulating evidence supports that AP-1 plays an important role in several severe disorders including cancer, fibrosis, and organ injury, as well as inflammatory disorders such as asthma, psoriasis, and rheumatoid arthritis. AP-1 has emerged as an actively pursued drug discovery target over the past decade. Excitingly, a selective AP-1 inhibitor T-5224 (51) has been investigated in phase II human clinical trials. Nevertheless, no effective AP-1 inhibitors have yet been approved for clinical use. Despite significant advances achieved in understanding AP-1 biology and function, as well as the identification of small molecules modulating AP-1 associated signaling pathways, medicinal chemistry efforts remain an urgent need to yield selective and efficacious AP-1 inhibitors as a viable therapeutic strategy for human diseases.

| S-EPMC4148154 | biostudies-literature

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