title: SB1578, a novel inhibitor of JAK2, FLT3, and c-Fms for the treatment of rheumatoid arthritis.
abstract: SB1578 is a novel, orally bioavailable JAK2 inhibitor with specificity for JAK2 within the JAK family and also potent activity against FLT3 and c-Fms. These three tyrosine kinases play a pivotal role in activation of pathways that underlie the pathogenesis of rheumatoid arthritis. SB1578 blocks the activation of these kinases and their downstream signaling in pertinent cells, leading to inhibition of pathological cellular responses. The biochemical and cellular activities of SB1578 translate into its high efficacy in two rodent models of arthritis. SB1578 not only prevents the onset of arthritis but is also potent in treating established disease in collagen-induced arthritis mice with beneficial effects on histopathological parameters of bone resorption and cartilage damage. SB1578 abrogates the inflammatory response and prevents the infiltration of macrophages and neutrophils into affected joints. It also leads to inhibition of Ag-presenting dendritic cells and inhibits the autoimmune component of the disease. In summary, SB1578 has a unique kinase spectrum, and its pharmacological profile provides a strong rationale for the ongoing clinical development in autoimmune diseases.
authors.affiliation: S*BIO Pte. Ltd., Singapore 117528. babitamadan@yahoo.com
authors.forename: Babita
authors.initials: B
authors.lastname: Madan
authors.forename: Kee Chuan
authors.initials: KC
authors.lastname: Goh
authors.forename: Stefan
authors.initials: S
authors.lastname: Hart
authors.forename: Anthony D
authors.initials: AD
authors.lastname: William
authors.forename: Ramesh
authors.initials: R
authors.lastname: Jayaraman
authors.forename: Kantharaj
authors.initials: K
authors.lastname: Ethirajulu
authors.forename: Brian W
authors.initials: BW
authors.lastname: Dymock
authors.forename: Jeanette M
authors.initials: JM
authors.lastname: Wood
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D004195:Disease Models, Animal; D006576:Heterocyclic Compounds, 4 or More Rings / Q000008:administration & dosage* / Q000627:therapeutic use; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D011917:Rats, Inbred Lew; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors*; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors*
chemical_list: C573839:15-(2-(pyrrolidin-1-yl)ethoxy)-7,12,25-trioxa-19,21,24-triazatetracyclo(18.3.1.1(2,5).1(14,18))hexacosa-1(24),2,4,9,14(26),15,17,20,22-nonaene; D006576:Heterocyclic Compounds, 4 or More Rings; C527539:FLT3 protein, rat; C497971:Flt3 protein, mouse; D016186:Receptor, Macrophage Colony-Stimulating Factor; D051941:fms-Like Tyrosine Kinase 3; C507926:Jak2 protein, mouse; C507927:Jak2 protein, rat; D053614:Janus Kinase 2