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Selective inhibition of JAK1 and JAK2 is efficacious in rodent models of arthritis: preclinical characterization of INCB028050.
- Source :
-
Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2010 May 01; Vol. 184 (9), pp. 5298-307. Date of Electronic Publication: 2010 Apr 02. - Publication Year :
- 2010
-
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.
- Subjects :
- Animals
Arthritis, Experimental immunology
Autoimmune Diseases drug therapy
Autoimmune Diseases enzymology
Autoimmune Diseases immunology
Cell Line
Disease Models, Animal
Drug Evaluation, Preclinical methods
Female
Humans
Inflammation Mediators antagonists & inhibitors
Inflammation Mediators physiology
Janus Kinase 1 physiology
Janus Kinase 2 physiology
Male
Mice
Mice, Inbred BALB C
Mice, Inbred DBA
Protein Kinase Inhibitors chemistry
Protein Kinase Inhibitors pharmacokinetics
Random Allocation
Rats
Rats, Inbred Lew
Signal Transduction drug effects
Signal Transduction immunology
Arthritis, Experimental drug therapy
Arthritis, Experimental enzymology
Janus Kinase 1 antagonists & inhibitors
Janus Kinase 2 antagonists & inhibitors
Protein Kinase Inhibitors administration & dosage
Subjects
Details
- Language :
- English
- ISSN :
- 1550-6606
- Volume :
- 184
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Journal of immunology (Baltimore, Md. : 1950)
- Publication Type :
- Academic Journal
- Accession number :
- 20363976
- Full Text :
- https://doi.org/10.4049/jimmunol.0902819