Discovery and characterization of 2-aminobenzimidazole derivatives as selective NOD1 inhibitors

Ricardo G. Correa; Pasha M. Khan; Nadav Askari; Dayong Zhai; Motti Gerlic; Brock Brown; Gavin Magnuson; Roberto Spreafico; Salvatore Albani; Eduard Sergienko; Paul W. Diaz; Gregory P. Roth; John C. Reed

doi:10.1016/j.chembiol.2011.06.009

Discovery and characterization of 2-aminobenzimidazole derivatives as selective NOD1 inhibitors

Ricardo G. Correa, Pasha M. Khan, Nadav Askari, Dayong Zhai, Motti Gerlic, Brock Brown, Gavin Magnuson, Roberto Spreafico, Salvatore Albani, Eduard Sergienko, Paul W. Diaz, Gregory P. Roth, John C. Reed

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	825-832
Number of pages	8
Journal	Chemistry and Biology
Volume	18
Issue number	7
DOIs	https://doi.org/10.1016/j.chembiol.2011.06.009
State	Published - 29 Jul 2011
Externally published	Yes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

All Science Journal Classification (ASJC) codes

Biochemistry
Molecular Medicine
Molecular Biology
Pharmacology
Drug Discovery
Clinical Biochemistry

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10.1016/j.chembiol.2011.06.009

Cite this

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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.",

author = "Correa, {Ricardo G.} and Khan, {Pasha M.} and Nadav Askari and Dayong Zhai and Motti Gerlic and Brock Brown and Gavin Magnuson and Roberto Spreafico and Salvatore Albani and Eduard Sergienko and Diaz, {Paul W.} and Roth, {Gregory P.} and Reed, {John C.}",

note = "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.",

year = "2011",

month = jul,

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doi = "10.1016/j.chembiol.2011.06.009",

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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.

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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 -

Discovery and characterization of 2-aminobenzimidazole derivatives as selective NOD1 inhibitors

Abstract

UN SDGs

All Science Journal Classification (ASJC) codes

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