Filgotinib (GLPG0634) is an orally-available, selective inhibitor of JAK1 (Janus kinase 1) for the treatment of rheumatoid arthritis and potentially other inflammatory diseases. Filgotinib (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. The JAK1 selective inhibitor GLPG0634 (Filgotinib) is a promising novel therapeutic with potential for oral treatment of rheumatoid arthritis and possibly other immune-inflammatory diseases. Filgotinib (GLPG0634) is currently in a Phase 2 study in Crohn's disease.
|Cell lines||T cells|
|Preparation method||T cell differentiation studies. PBMCs were isolated from buffy coats of healthy donors (Blood Transfusion Center, Red Cross, Leuven, Belgium) using density gradient centrifugation on Lymphoprep. Naive CD4+ T cells were further isolated by depletion of non–T helper and memory CD4+ T cells using a naive CD4+ T cell isolation kit II (Miltenyi Biotec). Isolated naive CD4+ T cells were stimulated with plate-bound anti-CD3 (3 μg/ml) and anti-CD28 (5 μg/ml) Abs in the presence of cytokines that drive differentiation into Th1, Th2, or Th17 Th subsets. For Th1 cell polarization, cells were cultured in the presence of 10 μg/ml anti–IL-4 Ab (MAB204; R&D Systems), 10 ng/ml IL-2 (R&D Systems), and 10 ng/ml IL-12 (R&D Systems) (17). For Th2 cell polarization, cells were cultured in the presence of 10 μg/ml anti–IFN-γ Ab (Becton Dickinson), 25 ng/ml IL-4 (R&D Systems), and 10 ng/ml IL-2 (17). For Th17 cell polarization, a mix of the following cytokines was used: 10 ng/ml IL-6 (R&D Systems), 10 ng/ml IL-1β (R&D Systems), 1 ng/ml TGF-β (PeproTech), and 100 ng/ml IL-23 (R&D Systems) (18). To monitor effects of compounds on T cell differentiation, compounds were added at indicated concentrations at the start of T cell differentiation. After 5 d, RNA was extracted using an RNeasy Mini kit (Qiagen), reverse transcribed, and the extent of Th subset differentiation was monitored by determining expression of IFN-γ (Th1 marker), IL-13 (Th2 marker), or IL-17F (Th17 marker) using real-time PCR on the ViiA7 thermocycler with predesigned TaqMan Assay-on-Demand gene expression primer/probe sets (Applied Biosystems). Gene expression was normalized to 18S and expressed as ΔCt values, with ΔCt = Ctgene − Ct18S or expressed as relative mRNA level of specific gene expression as obtained using the 2−ΔCt method.|
|Concentrations||10, 1, 0.1 or 0 μM|
|Incubation time||5 days|
|Animal models||therapeutic rat CIA model|
|Formulation||0.05 M acetic acid|
|Dosages||50 mg/kg twice daily for 14 d|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
Preclinical characterization of GLPG0634, a selective inhibitor of JAK1, for the treatment of inflammatory diseases.
Van Rompaey L, et al. J Immunol. 2013 Oct 1;191(7):3568-77. PMID: 24006460.
|Related JAK Products|
Ruxolitinib phosphate(INCB018424 phosphate) is the first potent, selective, JAK1/2 inhibitor to enter the clinic with IC50 of 3.3 nM/2.8 nM, >130-fold selectivity for JAK1/2 versus JAK3.
Oclacitinib is a novel inhibitor of JAK family members with IC50 ranging from 10 to 99 nM and JAK1-dependent cytokines with IC50 ranging from 36 to 249 nM, which did not inhibit a panel of 38 non-JAK kinases.
Baricitinib phosphate(INCB 028050; LY 3009104) is a selective JAK1 and JAK2 inhibitor with IC50 of 5.9 nM and 5.7 nM, ~70 and ~10-fold selective versus JAK3 and Tyk2, no inhibition to c-Met and Chk2.
Janex-1 is a cell-permeable, reversible, potent, ATP-competitive, and specific inhibitor of JAK3 (IC50 = 78 μM); has no effect on JAK1, JAK2, or Zap/Syk or SRC tyrosine kinases.
Decernotinib is a potent and selective Janus kinase 3 (JAK3) inhibitor with Ki of 2.5 nM; IC50 is 50-170 nM in cellular assays.
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