TY - JOUR
T1 - Discovery and characterization of 2-aminobenzimidazole derivatives as selective NOD1 inhibitors
AU - Correa, Ricardo G.
AU - Khan, Pasha M.
AU - Askari, Nadav
AU - Zhai, Dayong
AU - Gerlic, Motti
AU - Brown, Brock
AU - Magnuson, Gavin
AU - Spreafico, Roberto
AU - Albani, Salvatore
AU - Sergienko, Eduard
AU - Diaz, Paul W.
AU - Roth, Gregory P.
AU - Reed, John C.
N1 - Funding Information: The authors thank M. Hanaii, T. Siegfried, C. Wimer, M. Cuddy, M. Rossetti, H. Zhang, W. Yu (Sanford-Burnham Medical Research Institute, La Jolla, CA, USA, and Orlando, FL, USA), P. Gosalia, C. Gasior, E. Suyama, S. Vasile, C. Hassig, and T. Chung (Conrad Prebys Center for Chemical Genomics, La Jolla, CA, USA) for their assistance in this project. This work was supported by NIH R03 MH084844 and NIH Roadmap Initiative Grant U54 HG005033.
PY - 2011/7/29
Y1 - 2011/7/29
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=79960965328&partnerID=8YFLogxK
U2 - 10.1016/j.chembiol.2011.06.009
DO - 10.1016/j.chembiol.2011.06.009
M3 - مقالة
SN - 1074-5521
VL - 18
SP - 825
EP - 832
JO - Chemistry and Biology
JF - Chemistry and Biology
IS - 7
ER -
