期刊
SLAS DISCOVERY
卷 23, 期 6, 页码 554-560出版社
SAGE PUBLICATIONS INC
DOI: 10.1177/2472555218757180
关键词
kynurenine 3-monooxygenase; high-throughput screening; kynurenine; 3-hydroxykynurenine; neurodegeneration; NADPH fluorescence
资金
- High-throughput screening was performed as a fee-for-service at the Drug Discovery Centre, Children's Cancer Institute of Australia
- Alzheimer's Drug Discovery Foundation, New York, New York
Kynurenine 3-monooxygenase (KMO) is a well-validated therapeutic target for the treatment of neurodegenerative diseases, including Alzheimer's disease (AD) and Huntington's disease (HD). This work reports a facile fluorescence-based KMO assay optimized for high-throughput screening (HTS) that achieves a throughput approximately 20-fold higher than the fastest KMO assay currently reported. The screen was run with excellent performance (average Z' value of 0.80) from 110,000 compounds across 341 plates and exceeded all statistical parameters used to describe a robust HTS assay. A subset of molecules was selected for validation by ultra-high-performance liquid chromatography, resulting in the confirmation of a novel hit with an IC50 comparable to that of the well-described KMO inhibitor Ro-61-8048. A medicinal chemistry program is currently underway to further develop our novel KMO inhibitor scaffolds.
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