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A selective and potent CXCR3 antagonist SCH 546738 attenuates the development of autoimmune diseases and delays graft rejection

BACKGROUND: The CXCR3 receptor and its three interferon-inducible ligands (CXCL9, CXCL10 and CXCL11) have been implicated as playing a central role in directing a Th1 inflammatory response. Recent studies strongly support that the CXCR3 receptor is a very attractive therapeutic target for treating a...

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Autores principales: Jenh, Chung-Her, Cox, Mary Ann, Cui, Long, Reich, Eva-Pia, Sullivan, Lee, Chen, Shu-Cheng, Kinsley, David, Qian, Shiguang, Kim, Seong Heon, Rosenblum, Stuart, Kozlowski, Joseph, Fine, Jay S, Zavodny, Paul J, Lundell, Daniel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3298469/
https://www.ncbi.nlm.nih.gov/pubmed/22233170
http://dx.doi.org/10.1186/10.1186/1471-2172-13-2
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author Jenh, Chung-Her
Cox, Mary Ann
Cui, Long
Reich, Eva-Pia
Sullivan, Lee
Chen, Shu-Cheng
Kinsley, David
Qian, Shiguang
Kim, Seong Heon
Rosenblum, Stuart
Kozlowski, Joseph
Fine, Jay S
Zavodny, Paul J
Lundell, Daniel
author_facet Jenh, Chung-Her
Cox, Mary Ann
Cui, Long
Reich, Eva-Pia
Sullivan, Lee
Chen, Shu-Cheng
Kinsley, David
Qian, Shiguang
Kim, Seong Heon
Rosenblum, Stuart
Kozlowski, Joseph
Fine, Jay S
Zavodny, Paul J
Lundell, Daniel
author_sort Jenh, Chung-Her
collection PubMed
description BACKGROUND: The CXCR3 receptor and its three interferon-inducible ligands (CXCL9, CXCL10 and CXCL11) have been implicated as playing a central role in directing a Th1 inflammatory response. Recent studies strongly support that the CXCR3 receptor is a very attractive therapeutic target for treating autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis and psoriasis, and to prevent transplant rejection. We describe here the in vitro and in vivo pharmacological characterizations of a novel and potent small molecule CXCR3 antagonist, SCH 546738. RESULTS: In this study, we evaluated in vitro pharmacological properties of SCH 546738 by radioligand receptor binding and human activated T cell chemotaxis assays. In vivo efficacy of SCH 546738 was determined by mouse collagen-induced arthritis, rat and mouse experimental autoimmune encephalomyelitis, and rat cardiac transplantation models. We show that SCH 546738 binds to human CXCR3 with a high affinity of 0.4 nM. In addition, SCH 546738 displaces radiolabeled CXCL10 and CXCL11 from human CXCR3 with IC(50 )ranging from 0.8 to 2.2 nM in a non-competitive manner. SCH 546738 potently and specifically inhibits CXCR3-mediated chemotaxis in human activated T cells with IC(90 )about 10 nM. SCH 546738 attenuates the disease development in mouse collagen-induced arthritis model. SCH 546738 also significantly reduces disease severity in rat and mouse experimental autoimmune encephalomyelitis models. Furthermore, SCH 546738 alone achieves dose-dependent prolongation of rat cardiac allograft survival. Most significantly, SCH 546738 in combination with CsA supports permanent engraftment. CONCLUSIONS: SCH 546738 is a novel, potent and non-competitive small molecule CXCR3 antagonist. It is efficacious in multiple preclinical disease models. These results demonstrate that therapy with CXCR3 antagonists may serve as a new strategy for treatment of autoimmune diseases, including rheumatoid arthritis and multiple sclerosis, and to prevent transplant rejection.
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spelling pubmed-32984692012-03-10 A selective and potent CXCR3 antagonist SCH 546738 attenuates the development of autoimmune diseases and delays graft rejection Jenh, Chung-Her Cox, Mary Ann Cui, Long Reich, Eva-Pia Sullivan, Lee Chen, Shu-Cheng Kinsley, David Qian, Shiguang Kim, Seong Heon Rosenblum, Stuart Kozlowski, Joseph Fine, Jay S Zavodny, Paul J Lundell, Daniel BMC Immunol Research Article BACKGROUND: The CXCR3 receptor and its three interferon-inducible ligands (CXCL9, CXCL10 and CXCL11) have been implicated as playing a central role in directing a Th1 inflammatory response. Recent studies strongly support that the CXCR3 receptor is a very attractive therapeutic target for treating autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis and psoriasis, and to prevent transplant rejection. We describe here the in vitro and in vivo pharmacological characterizations of a novel and potent small molecule CXCR3 antagonist, SCH 546738. RESULTS: In this study, we evaluated in vitro pharmacological properties of SCH 546738 by radioligand receptor binding and human activated T cell chemotaxis assays. In vivo efficacy of SCH 546738 was determined by mouse collagen-induced arthritis, rat and mouse experimental autoimmune encephalomyelitis, and rat cardiac transplantation models. We show that SCH 546738 binds to human CXCR3 with a high affinity of 0.4 nM. In addition, SCH 546738 displaces radiolabeled CXCL10 and CXCL11 from human CXCR3 with IC(50 )ranging from 0.8 to 2.2 nM in a non-competitive manner. SCH 546738 potently and specifically inhibits CXCR3-mediated chemotaxis in human activated T cells with IC(90 )about 10 nM. SCH 546738 attenuates the disease development in mouse collagen-induced arthritis model. SCH 546738 also significantly reduces disease severity in rat and mouse experimental autoimmune encephalomyelitis models. Furthermore, SCH 546738 alone achieves dose-dependent prolongation of rat cardiac allograft survival. Most significantly, SCH 546738 in combination with CsA supports permanent engraftment. CONCLUSIONS: SCH 546738 is a novel, potent and non-competitive small molecule CXCR3 antagonist. It is efficacious in multiple preclinical disease models. These results demonstrate that therapy with CXCR3 antagonists may serve as a new strategy for treatment of autoimmune diseases, including rheumatoid arthritis and multiple sclerosis, and to prevent transplant rejection. BioMed Central 2012-01-10 /pmc/articles/PMC3298469/ /pubmed/22233170 http://dx.doi.org/10.1186/10.1186/1471-2172-13-2 Text en Copyright ©2012 Jenh et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 http://www.biomedcentral.com/info/authors/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://www.biomedcentral.com/info/authors/
spellingShingle Research Article
Jenh, Chung-Her
Cox, Mary Ann
Cui, Long
Reich, Eva-Pia
Sullivan, Lee
Chen, Shu-Cheng
Kinsley, David
Qian, Shiguang
Kim, Seong Heon
Rosenblum, Stuart
Kozlowski, Joseph
Fine, Jay S
Zavodny, Paul J
Lundell, Daniel
A selective and potent CXCR3 antagonist SCH 546738 attenuates the development of autoimmune diseases and delays graft rejection
title A selective and potent CXCR3 antagonist SCH 546738 attenuates the development of autoimmune diseases and delays graft rejection
title_full A selective and potent CXCR3 antagonist SCH 546738 attenuates the development of autoimmune diseases and delays graft rejection
title_fullStr A selective and potent CXCR3 antagonist SCH 546738 attenuates the development of autoimmune diseases and delays graft rejection
title_full_unstemmed A selective and potent CXCR3 antagonist SCH 546738 attenuates the development of autoimmune diseases and delays graft rejection
title_short A selective and potent CXCR3 antagonist SCH 546738 attenuates the development of autoimmune diseases and delays graft rejection
title_sort selective and potent cxcr3 antagonist sch 546738 attenuates the development of autoimmune diseases and delays graft rejection
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3298469/
https://www.ncbi.nlm.nih.gov/pubmed/22233170
http://dx.doi.org/10.1186/10.1186/1471-2172-13-2
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