Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 2, Issue 10, Pages 780-785Publisher
AMER CHEMICAL SOC
DOI: 10.1021/ml200158b
Keywords
NOD1; NF-kappa B activation; 2-aminobenzimidazole; hit-to-probe; ML130; MLPCN
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Funding
- Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research NIH [5U54 HG005033, 1 R03 MH084844]
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NOD1 (nucleotide-binding oligomerization domain 1) protein is a member of the NLR (NACHT and leucine rich repeat domain containing proteins) protein family, which plays a key role in innate immunity as a sensor of specific microbial components derived from bacterial peptidoglycans and induction of inflammatory responses. Mutations in NOD proteins have been associated with various inflammatory diseases that affect NF-kappa B (nuclear factor kappa B) activity, a major signaling pathway involved in apoptosis, inflammation, and immune response. A luciferase-based reporter gene assay was utilized in a high-throughput screening program conducted under the NIH-sponsored Molecular Libraries Probe Production Center Network program to identify the active scaffolds. Herein, we report the chemical synthesis, structure-activity relationship studies, downstream counterscreens, secondary assay data, and pharmacological profiling of the 2-aminobenzimidazole lead (compound 1c, ML130) as a potent and selective inhibitor of NOD 1-induced NF-kappa B activation.
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