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

ABSTRACT: Targeting of the NOTCH transcription complex by a novel small molecule inhibitor CB-103 in HPB-ALL cells

PROVIDER: PRJNA596947 | ENA |

REPOSITORIES: ENA

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

Project description:We used microarrays to study the transcriptional networks controlled by CB-103 in HPB-ALL human cell line.

2020-12-19 | GSE142406 | GEO

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

Project description:We used microarrays to study the transcriptional networks controlled by CB-103 in KOPT-K1 human cell line.

2020-12-19 | GSE142407 | GEO

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

| PRJNA596943 | ENA

CRISPR/Cas9 screen of T-ALL cells (DND-41) in the presence of DMSO, CB-103 or GSI (DAPT).

Project description:The efficacy of targeted therapies for treatment of cancer patients is often limited by development of drug resistance. Potential resistance mechanisms to pharmacological Notch1 inhibition mediated by GSI or CB-103 in T-ALL are currently unclear. Thus, we performed a genome-wide loss-of-function (LoF) CRISPR/Cas9 screen to identify genes responsible for resistance to Notch inhibition and novel combination therapies for efficient treatment of human T-ALL. We used a Notch-dependent human T-ALL cell line, DND-41, which responds moderately to both GSI and CB-103 treatment in vitro. DND-41 cells stably expressing Cas9 were infected with human GeCKO v2 CRIPSR libraries, containing 123,411 sgRNAs targeting 19,050 genes and treated with either vehicle, GSI or CB-103 for 21 days enabling both positive and negative selection of sgRNAs.

2023-06-26 | GSE221576 | 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 (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

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

| PRJNA596946 | ENA

Study of CB-103 in Adult Patients With Advanced or Metastatic Solid Tumours and Haematological Malignancies

Project description:This is a phase I/II, non randomized, open-label, dose escalation study to investigate the safety, tolerability and preliminary efficacy of CB-103.

| 2265066 | ecrin-mdr-crc

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

HCT116 cells treated with the p97 inhibitior CB-5083

Project description:The goal of this study was to analyze differential gene expression 8 hr after treatment of CB-5083, a small molecule inhibitor of p97 (VCP), in HCT116 cells grown in culture. DMSO treated cells were compared to cells treated with 1uM CB-5083 after 8 hr.

2015-11-09 | E-GEOD-73588 | biostudies-arrayexpress

HCT116 cells treated with the p97 inhibitior CB-5083

Project description:The goal of this study was to analyze differential gene expression 8 hr after treatment of CB-5083, a small molecule inhibitor of p97 (VCP), in HCT116 cells grown in culture.

2015-11-09 | GSE73588 | GEO

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