THU0541 Anti-Inflammatory Activity of A Novel Small Molecule Inhibitor of Pikfvye, A Class III PI Kinase
| Autor: | E. Imamura, Hidekazu Mizuhara, Y. Kaneko-Kobayashi, Masatoshi Yuri, Masaomi Terajima, Yasuyuki Higashi, Kazuyuki Hattori, T. Ishikawa, N. Seki, Naoto Nakamura |
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| Rok vydání: | 2014 |
| Předmět: |
MHC class II
biology medicine.drug_class business.industry medicine.medical_treatment Immunology B-cell receptor Inflammation Pharmacology General Biochemistry Genetics and Molecular Biology Anti-inflammatory Proinflammatory cytokine PIKFYVE Cytokine Rheumatology medicine biology.protein Immunology and Allergy Tumor necrosis factor alpha medicine.symptom business |
| Zdroj: | Annals of the Rheumatic Diseases. 73:370.1-370 |
| ISSN: | 1468-2060 0003-4967 |
| DOI: | 10.1136/annrheumdis-2014-eular.1310 |
| Popis: | Background Aberrant production of proinflammatory cytokines is associated with various chronic inflammatory diseases, and their functional inhibition is considered beneficial. We previously reported the discovery of novel small molecule inhibitors of PIKfyve, AS2677131 and AS2795440. These compounds were found as IL-12p40 inhibitors by phenotypic screening in IFNγ/LPS-activated mouse macrophage cell line RAW264.7, but their pharmacological properties and therapeutic potential in chronic inflammation have not been fully explored. Objectives The aim of this study was to characterize in vitro and in vivo anti-inflammatory activity of a novel PIKfyve inhibitor, AS2795440. Methods In vitro and in vivo TLR ligand-induced cytokine production assays were conducted in RAW264.7 cells, mouse perioneal macrophages, and rat acute inflammation model. Concentrations of IL-12p40, IL-6, and TNFα were measured in culture supernatants or plasma by ELISA. B cell receptor (BCR)-mediated B cell activation activity was examined by measuring MHC class II expression in whole blood from rats treated with AS2795440. To evaluate therapeutic potential in chronic inflammation, rat adjuvant-induced arthritis (AIA) was examined. AS2795440 was daily administered from the day after adjuvant injection. All animal experimental procedures were approved by the Institutional Animal Care and Use Committee of Astellas Pharma Inc. Results AS2795440 inhibited the production of TLR ligand-induced proinflammatory cytokines, IL-12p40 and IL-6 but not TNFα, and expression of IgM-induced MHC class II on B cells, dose-dependently. In a rat AIA, AS2795440 (1-10 mg/kg) significantly suppressed the paw swelling and bone destruction, dose-dependently. Conclusions These results indicate that AS2795440 is a potent PIKfyve inhibitor, which has unique anti-inflammatory activity, such as inhibition of proinflammatory cytokine production and B cell activation, and has a potential therapeutic benefit in chronic inflammatory diseases. Disclosure of Interest : M. Terajima Employee of: Astellas Pharma Inc., Y. Kaneko-Kobayashi Employee of: Astellas Pharma Inc., H. Mizuhara Employee of: Astellas Pharma Inc., T. Ishikawa Employee of: Astellas Pharma Inc., E. Imamura Employee of: Astellas Pharma Inc., K. Hattori Employee of: Astellas Pharma Inc., N. Nakamura Employee of: Astellas Pharma Inc., M. Yuri Employee of: Astellas Pharma Inc., Y. Higashi Employee of: Astellas Pharma Inc., N. Seki Employee of: Astellas Pharma Inc. DOI 10.1136/annrheumdis-2014-eular.1310 |
| Databáze: | OpenAIRE |
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