title: KR33426, [2-(2,5-dichlorophenyl)-5-methyloxazol-4yl]carbonylguanidine, is a novel compound to be effective on mouse systemic lupus erythematosus.
abstract: B cell-activating factor (BAFF) is a key regulator of B lymphocyte development. Signals from BAFF are transmitted through binding to a specific BAFF receptor (BAFF-R). Here, we established screening method to find a specific inhibitor for the interference of BAFF-BAFF-R interactions. We screened oxazole-4-carbonylguanidine derivatives and selected KR33426, [2-(2,5-dichlorophenyl)-5-methyloxazol-4yl]carbonylguanidine, as a candidate to interfere BAFF-BAFF-R interactions. KR33426 inhibited BAFF-mediated anti-apoptotic effect on splenocytes as judged by hypodiploid cell formation. KR33426 also increased the degradation of procaspase-3 that was inhibited by BAFF protein. In addition, we examined whether KR33426 was effective on the treatment of systemic lupus erythematosus-like symptom in MRL(lpr/lpr) mouse. When 5 or 10mg/kg KR33426 was intraperitoneally administered to MRL(lpr/lpr) mice for 4 weeks, histopathological changes were ameliorated in the narrowed space between renal glomerulus and glomerulus capsule. KR33426 reduced B220(+) B cell population and B cell mitogen, lipopolysaccharide-stimulated lymphocyte proliferation in splenocytes. KR33426 attenuated an increase in CD43(-)IgM(+) immature pro-B and a decrease in CD21(+) IgM(+) T2-B and IgD(+) IgM(-)recirculating-B cells on B cell development. Data show that KR33426 inhibits BAFF-BAFF-R interactions and it is effective on the treatment of systemic lupus erythematosus-like symptom in MRL(lpr/lpr) mice. Thus, it suggests that KR33426 is a novel candidate to develop anti-autoimmune therapeutics by the interference of BAFF-BAFF-R interactions, specifically.
authors.affiliation: Department of Bioscience and Biotechnology, Sejong University, Seoul 143-747, Republic of Korea.
authors.forename: Geun-Hee
authors.initials: GH
authors.lastname: Lee
authors.forename: Jin-Mi
authors.initials: JM
authors.lastname: Oh
authors.forename: Hyun-Sun
authors.initials: HS
authors.lastname: Kim
authors.forename: Won-Kee
authors.initials: WK
authors.lastname: Yoon
authors.forename: Kyu Yang
authors.initials: KY
authors.lastname: Yi
authors.forename: Young
authors.initials: Y
authors.lastname: Yang
authors.forename: Seung-Hyun
authors.initials: SH
authors.lastname: Han
authors.forename: Sunkyung
authors.initials: S
authors.lastname: Lee
authors.forename: Eun-Yi
authors.initials: EY
authors.lastname: Moon
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053264:B-Cell Activating Factor / Q000378:metabolism; D053265:B-Cell Activation Factor Receptor / Q000378:metabolism; D001402:B-Lymphocytes / Q000187:drug effects / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005260:Female; D006146:Guanidines / Q000494:pharmacology* / Q000627:therapeutic use; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D010080:Oxazoles / Q000494:pharmacology*; D013154:Spleen / Q000276:immunology
chemical_list: D053264:B-Cell Activating Factor; D053265:B-Cell Activation Factor Receptor; D006146:Guanidines; C569343:KR33426; D010080:Oxazoles