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Pharmacological disruption of the Notch transcription factor complex

ABSTRACT: Pharmacological disruption of the Notch transcription factor complex

PROVIDER: PRJNA623559 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11497500.fastq.gz	Fastqsanger.gz
	SRR11497501.fastq.gz	Fastqsanger.gz
	SRR11497502.fastq.gz	Fastqsanger.gz
	SRR11497503.fastq.gz	Fastqsanger.gz
	SRR11497504.fastq.gz	Fastqsanger.gz

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Pharmacological disruption of the Notch transcription factor complex

Project description:Notch pathway signaling is implicated in several human cancers. Aberrant activation and mutations of Notch signaling components are linked to tumor initiation, maintenance and resistance to cancer therapy. Several strategies, such as monoclonal antibodies (MAbs) against Notch ligands and receptors, as well as small molecule -secretase inhibitors (GSIs), have been developed to interfere with Notch receptor activation at proximal points in the pathway. However, the use of drug-like small molecules to target the downstream mediators of Notch signaling, the Notch transcription activation complex, remains largely unexplored. Using a Notch signaling dependent co-culture system, we developed a high-throughput small molecule screening assay. Herein we report the discovery of an orally active small molecule inhibitor (termed CB-103) of the Notch transcription activation complex. We show that CB-103 inhibits Notch signaling in primary human T-ALL and other Notch-dependent human tumor cell lines, and concomitantly induces cell cycle arrest, thereby impairing proliferation. Notably, CB-103 has the ability to downregulate Notch signaling in GSI-resistant human tumor cell lines that harbor chromosomal translocations and rearrangements in Notch genes. CB-103 mimics Notch loss-of-function phenotypes in flies and mice, retarding tumor growth in xenograft models of breast cancer and patient-derived xenograft models of human leukemia, notably without causing the frequently observed dose-limiting intestinal toxicity induced by other Notch inhibitors. In summary, we describe a pharmacological strategy to interfere with Notch signaling by disrupting the transcriptional regulatory complex it assembles, with therapeutic potential for the treatment of human tumors.

2020-12-19 | GSE148228 | GEO

Pharmacological disruption of the Notch transcription factor complex.

Project description:Notch pathway signaling is implicated in several human cancers. Aberrant activation and mutations of Notch signaling components are linked to tumor initiation, maintenance, and resistance to cancer therapy. Several strategies, such as monoclonal antibodies against Notch ligands and receptors, as well as small-molecule γ-secretase inhibitors (GSIs), have been developed to interfere with Notch receptor activation at proximal points in the pathway. However, the use of drug-like small molecules to target the downstream mediators of Notch signaling, the Notch transcription activation complex, remains largely unexplored. Here, we report the discovery of an orally active small-molecule inhibitor (termed CB-103) of the Notch transcription activation complex. We show that CB-103 inhibits Notch signaling in primary human T cell acute lymphoblastic leukemia and other Notch-dependent human tumor cell lines, and concomitantly induces cell cycle arrest and apoptosis, thereby impairing proliferation, including in GSI-resistant human tumor cell lines with chromosomal translocations and rearrangements in Notch genes. CB-103 produces Notch loss-of-function phenotypes in flies and mice and inhibits the growth of human breast cancer and leukemia xenografts, notably without causing the dose-limiting intestinal toxicity associated with other Notch inhibitors. Thus, we describe a pharmacological strategy that interferes with Notch signaling by disrupting the Notch transcription complex and shows therapeutic potential for treating Notch-driven cancers.

| S-EPMC7368267 | biostudies-literature

Pharmacological Repositioning of the transcription factor PU.1

Project description:Pharmacological Repositioning of the transcription factor PU.1

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Pharmacological Repositioning of the transcription factor PU.1 [CUTnTag]

Project description:Pharmacological Repositioning of the transcription factor PU.1 [CUTnTag]

| PRJNA1111390 | ENA

Pharmacological Repositioning of the transcription factor PU.1 [ChIP-seq]

Project description:Pharmacological Repositioning of the transcription factor PU.1 [ChIP-seq]

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Pharmacological Repositioning of the transcription factor PU.1 [PRO-seq]

Project description:Pharmacological Repositioning of the transcription factor PU.1 [PRO-seq]

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Pharmacological Repositioning of the transcription factor PU.1 [ATAC-seq]

Project description:Pharmacological Repositioning of the transcription factor PU.1 [ATAC-seq]

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Pharmacological Repositioning of the transcription factor PU.1 [RNA-seq]

Project description:Pharmacological Repositioning of the transcription factor PU.1 [RNA-seq]

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Notch Signaling Enhances Bone Regeneration in the Zebrafish Mandible

Project description:Loss or damage to the mandible due to trauma, treatment of oral malignancies, and other diseases is currently treated using bone grafting techniques that suffer from numerous shortcomings and contraindications. Zebrafish naturally heal large injuries to their mandibular bone, and thus offer an opportunity to understand how to boost intrinsic healing ability. Using a novel her6:mCherry Notch reporter, we show that canonical Notch signaling is induced during the initial stages of cartilage callus formation in both mesenchymal cells and chondrocytes. We also show that modulation of Notch signaling during the initial postoperative period results in lasting changes to regenerate bone quantity one month later. Notch signaling is required for mandibular bone healing, as pharmacological inhibition of Notch signaling blocks cartilage callus formation and results in non-union. Conversely, conditional transgenic activation of Notch signaling accelerates regenerative ossification. Mechanistically, we report that postoperative Notch signaling regulates multiple phases of chondroid regeneration and patterns callus metabolic landscape. Given conserved functions of Notch signaling in bone repair across vertebrates, we propose that targeted activation of Notch signaling during the early phases of bone healing may have therapeutic value.

2022-03-07 | PXD027280 | Pride

Notch-Jagged signaling complex defined by an interaction mosaic

Project description:The Notch signaling system links cellular fate to that of its neighbors, driving proliferation, apoptosis, and cell differentiation in metazoan organisms, whereas dysfunction leads to debilitating developmental disorders and cancers. Here we probe the molecular architecture of mammalian Notch1 full ectodomain in complex with the canonical ligand Jagged1 using cross-linking mass spectrometry (XL-MS). Our data reveals that three Jagged1 sites, C2-epidermal growth factor (EGF) 1, EGF10 and cysteine-rich domain (CRD), are in proximity to the Notch1 negative regulatory region (NRR) in the Notch1-Jagged1 full ectodomain complex. We verified direct interactions and identified additional interacting regions by quantitative-binding experiments. In addition, XL-MS and structural analysis reveal Notch1 and Jagged1 ectodomain intramolecular interactions and structural flexibility that support the formation of backfolded architectures. Together the data suggest a direct and intricate role for the different extracellular regions of Notch1 and Jagged1 in the activation and regulation of Notch1 signaling.

2021-07-08 | PXD023072 | Pride

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