title: Selective inhibition of JAK1 and JAK2 is efficacious in rodent models of arthritis: preclinical characterization of INCB028050.
abstract: Inhibiting signal transduction induced by inflammatory cytokines offers a new approach for the treatment of autoimmune diseases such as rheumatoid arthritis. Kinase inhibitors have shown promising oral disease-modifying antirheumatic drug potential with efficacy similar to anti-TNF biologics. Direct and indirect inhibition of the JAKs, with small molecule inhibitors like CP-690,550 and INCB018424 or neutralizing Abs, such as the anti-IL6 receptor Ab tocilizumab, have demonstrated rapid and sustained improvement in clinical measures of disease, consistent with their respective preclinical experiments. Therefore, it is of interest to identify optimized JAK inhibitors with unique profiles to maximize therapeutic opportunities. INCB028050 is a selective orally bioavailable JAK1/JAK2 inhibitor with nanomolar potency against JAK1 (5.9 nM) and JAK2 (5.7 nM). INCB028050 inhibits intracellular signaling of multiple proinflammatory cytokines including IL-6 and IL-23 at concentrations <50 nM. Significant efficacy, as assessed by improvements in clinical, histologic and radiographic signs of disease, was achieved in the rat adjuvant arthritis model with doses of INCB028050 providing partial and/or periodic inhibition of JAK1/JAK2 and no inhibition of JAK3. Diminution of inflammatory Th1 and Th17 associated cytokine mRNA levels was observed in the draining lymph nodes of treated rats. INCB028050 was also effective in multiple murine models of arthritis, with no evidence of suppression of humoral immunity or adverse hematologic effects. These data suggest that fractional inhibition of JAK1 and JAK2 is sufficient for significant activity in autoimmune disease models. Clinical evaluation of INCB028050 in RA is ongoing.
authors.affiliation: Drug Discovery, Incyte Corporation, Wilmington, DE 19880, USA. jfridman@incyte.com
authors.forename: Jordan S
authors.initials: JS
authors.lastname: Fridman
authors.forename: Peggy A
authors.initials: PA
authors.lastname: Scherle
authors.forename: Robert
authors.initials: R
authors.lastname: Collins
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Burn
authors.forename: Yanlong
authors.initials: Y
authors.lastname: Li
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Maryanne B
authors.initials: MB
authors.lastname: Covington
authors.forename: Beth
authors.initials: B
authors.lastname: Thomas
authors.forename: Paul
authors.initials: P
authors.lastname: Collier
authors.forename: Margaret F
authors.initials: MF
authors.lastname: Favata
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Wen
authors.forename: Jack
authors.initials: J
authors.lastname: Shi
authors.forename: Ryan
authors.initials: R
authors.lastname: McGee
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Haley
authors.forename: Stacey
authors.initials: S
authors.lastname: Shepard
authors.forename: James D
authors.initials: JD
authors.lastname: Rodgers
authors.forename: Swamy
authors.initials: S
authors.lastname: Yeleswaram
authors.forename: Greg
authors.initials: G
authors.lastname: Hollis
authors.forename: Robert C
authors.initials: RC
authors.lastname: Newton
authors.forename: Brian
authors.initials: B
authors.lastname: Metcalf
authors.forename: Steven M
authors.initials: SM
authors.lastname: Friedman
authors.forename: Kris
authors.initials: K
authors.lastname: Vaddi
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000201:enzymology* / Q000276:immunology; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology; D002460:Cell Line; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000502:physiology; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors* / Q000502:physiology; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000502:physiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D011897:Random Allocation; D051381:Rats; D011917:Rats, Inbred Lew; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology
chemical_list: D018836:Inflammation Mediators; D047428:Protein Kinase Inhibitors; C507906:Jak1 protein, rat; C507927:Jak2 protein, rat; D053613:Janus Kinase 1; D053614:Janus Kinase 2