title: Preclinical characterization of GLPG0634, a selective inhibitor of JAK1, for the treatment of inflammatory diseases.
abstract: The JAKs receive continued interest as therapeutic targets for autoimmune, inflammatory, and oncological diseases. JAKs play critical roles in the development and biology of the hematopoietic system, as evidenced by mouse and human genetics. JAK1 is critical for the signal transduction of many type I and type II inflammatory cytokine receptors. In a search for JAK small molecule inhibitors, GLPG0634 was identified as a lead compound belonging to a novel class of JAK inhibitors. It displayed a JAK1/JAK2 inhibitor profile in biochemical assays, but subsequent studies in cellular and whole blood assays revealed a selectivity of ∼30-fold for JAK1- over JAK2-dependent signaling. GLPG0634 dose-dependently inhibited Th1 and Th2 differentiation and to a lesser extent the differentiation of Th17 cells in vitro. GLPG0634 was well exposed in rodents upon oral dosing, and exposure levels correlated with repression of Mx2 expression in leukocytes. Oral dosing of GLPG0634 in a therapeutic set-up in a collagen-induced arthritis model in rodents resulted in a significant dose-dependent reduction of the disease progression. Paw swelling, bone and cartilage degradation, and levels of inflammatory cytokines were reduced by GLPG0634 treatment. Efficacy of GLPG0634 in the collagen-induced arthritis models was comparable to the results obtained with etanercept. In conclusion, the JAK1 selective inhibitor GLPG0634 is a promising novel therapeutic with potential for oral treatment of rheumatoid arthritis and possibly other immune-inflammatory diseases.
authors.affiliation: Departement of In Vitro Pharmacology, Galapagos NV, 2800 Mechelen, Belgium.
authors.forename: Luc
authors.initials: L
authors.lastname: Van Rompaey
authors.forename: René
authors.initials: R
authors.lastname: Galien
authors.forename: Ellen M
authors.initials: EM
authors.lastname: van der Aar
authors.forename: Philippe
authors.initials: P
authors.lastname: Clement-Lacroix
authors.forename: Luc
authors.initials: L
authors.lastname: Nelles
authors.forename: Bart
authors.initials: B
authors.lastname: Smets
authors.forename: Liên
authors.initials: L
authors.lastname: Lepescheux
authors.forename: Thierry
authors.initials: T
authors.lastname: Christophe
authors.forename: Katja
authors.initials: K
authors.lastname: Conrath
authors.forename: Nick
authors.initials: N
authors.lastname: Vandeghinste
authors.forename: Béatrice
authors.initials: B
authors.lastname: Vayssiere
authors.forename: Steve
authors.initials: S
authors.lastname: De Vos
authors.forename: Stephen
authors.initials: S
authors.lastname: Fletcher
authors.forename: Reginald
authors.initials: R
authors.lastname: Brys
authors.forename: Gerben
authors.initials: G
authors.lastname: van 't Klooster
authors.forename: Jean H M
authors.initials: JH
authors.lastname: Feyen
authors.forename: Christel
authors.initials: C
authors.lastname: Menet
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005260:Female; D020868:Gene Silencing; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism*; D020128:Inhibitory Concentration 50; D015850:Interleukin-6 / Q000494:pharmacology; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D050794:STAT1 Transcription Factor / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D014230:Triazoles / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: C584571:GLPG0634; D015850:Interleukin-6; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D050794:STAT1 Transcription Factor; D014230:Triazoles; D053613:Janus Kinase 1