title: Discovery and characterization of 2-aminobenzimidazole derivatives as selective NOD1 inhibitors.
abstract: NLR family proteins play important roles in innate immune response. NOD1 (NLRC1) activates various signaling pathways including NF-κB in response to bacterial ligands. Hereditary polymorphisms in the NOD1 gene are associated with asthma, inflammatory bowel disease, and other disorders. Using a high throughput screening (HTS) assay measuring NOD1-induced NF-κB reporter gene activity, followed by multiple downstream counter screens that eliminated compounds impacting other NF-κB effectors, 2-aminobenzimidazole compounds were identified that selectively inhibit NOD1. Mechanistic studies of a prototypical compound, Nodinitib-1 (ML130; CID-1088438), suggest that these small molecules cause conformational changes of NOD1 in vitro and alter NOD1 subcellular targeting in cells. Altogether, this inaugural class of inhibitors provides chemical probes for interrogating mechanisms regulating NOD1 activity and tools for exploring the roles of NOD1 in various infectious and inflammatory diseases.
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors.forename: Ricardo G
authors.initials: RG
authors.lastname: Correa
authors.forename: Pasha M
authors.initials: PM
authors.lastname: Khan
authors.forename: Nadav
authors.initials: N
authors.lastname: Askari
authors.forename: Dayong
authors.initials: D
authors.lastname: Zhai
authors.forename: Motti
authors.initials: M
authors.lastname: Gerlic
authors.forename: Brock
authors.initials: B
authors.lastname: Brown
authors.forename: Gavin
authors.initials: G
authors.lastname: Magnuson
authors.forename: Roberto
authors.initials: R
authors.lastname: Spreafico
authors.forename: Salvatore
authors.initials: S
authors.lastname: Albani
authors.forename: Eduard
authors.initials: E
authors.lastname: Sergienko
authors.forename: Paul W
authors.initials: PW
authors.lastname: Diaz
authors.forename: Gregory P
authors.initials: GP
authors.lastname: Roth
authors.forename: John C
authors.initials: JC
authors.lastname: Reed
mesh_terms: D001562:Benzimidazoles / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D017930:Genes, Reporter / Q000187:drug effects; D057166:High-Throughput Screening Assays; D006801:Humans; D016328:NF-kappa B / Q000235:genetics; D053474:Nod1 Signaling Adaptor Protein / Q000037:antagonists & inhibitors* / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D001562:Benzimidazoles; D016328:NF-kappa B; D053474:Nod1 Signaling Adaptor Protein; C027391:2-aminobenzimidazole