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

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

ORGANISM(S): Homo sapiens

PROVIDER: GSE142408 | GEO | 2020/12/19

REPOSITORIES: GEO

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Targeting of the NOTCH transcription complex by a novel small molecule inhibitor CB-103 in KOPT-K1 cells

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

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

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Targeting of the NOTCH transcription complex by a novel small molecule inhibitor CB-103 in KOPT-K1 cells

Project description:Targeting of the NOTCH transcription complex by a novel small molecule inhibitor CB-103 in KOPT-K1 cells

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Disruption of NOTCH signaling by a small molecule inhibitor of the transcription factor RBPJ.

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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.

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

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

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