ArticleCombinatorial chemistry & high throughput screening2013
A novel high throughput 1536-well Notch1 γ -secretase AlphaLISA assay.
Article in Combinatorial chemistry & high throughput screening, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed, 9 citations in OpenAlex.
- γ-Secretase Partitioning into Lipid Bilayers Remodels Membrane Microdomains after Direct Insertion.Langmuir : the ACS journal of surfaces and colloids · 2020Article
- Noncompetitive Homogeneous Detection of Small Molecules Using Synthetic Nanopeptamer-Based Luminescent Oxygen Channeling.Analytical chemistry · 2018Article
- Development of a simple measurement method for GluR2 protein expression as an index of neuronal vulnerability.Toxicology reports · 2015Article
- Development of CBAP-BPyne, a probe for γ-secretase and presenilinase.MedChemComm · 2014Article
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
Abstract
The Notch pathway plays a crucial role in cell fate decisions through controlling various cellular processes. Overactive Notch signal contributes to cancer development from leukemias to solid tumors. γ-Secretase is an intramembrane protease responsible for the final proteolytic step of Notch that releases the membrane-tethered Notch fragment for signaling. Therefore, γ-secretase is an attractive drug target in treating Notch-mediated cancers. However, the absence of high throughput γ-secretase assay using Notch substrate has limited the identification and development of γ- secretase inhibitors that specifically target the Notch signaling pathway. Here, we report on the development of a 1536- well γ-secretase assay using a biotinylated recombinant Notch1 substrate. We effectively assimilated and miniaturized this newly developed Notch1 substrate with the AlphaLISA detection technology and demonstrated its robustness with a calculated Z' score of 0.66. We further validated this optimized assay by performing a pilot screening against a chemical library consisting of ~5,600 chemicals and identified known γ-secretase inhibitors e.g. DAPT, and Calpeptin; as well as a novel γ-secretase inhibitor referred to as KD-I-085. This assay is the first reported 1536-well AlphaLISA format and represents a novel high throughput Notch1-γ-secretase assay, which provides an unprecedented opportunity to discover Notch-selective γ-secretase inhibitors that can be potentially used for the treatment of cancer and other human disorders.
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Registered trials
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