Pharmacological properties of JTE-052: a novel potent JAK inhibitor that suppresses various inflammatory responses in vitro and in vivo.
OBJECTIVE
To evaluate the pharmacological properties of JTE-052, a novel Janus kinase (JAK) inhibitor.


METHODS
The JAK inhibitory activity of JTE-052 was evaluated using recombinant human enzymes. The inhibitory effects on cytokine signaling pathways were evaluated using primary human inflammatory cells. The in vivo efficacy and potency of JTE-052 were examined in a mouse interleukin (IL)-2-induced interferon (IFN)-γ production model and a rat collagen-induced arthritis model.


RESULTS
JTE-052 inhibited the JAK1, JAK2, JAK3, and tyrosine kinase (Tyk)2 enzymes in an adenosine triphosphate (ATP)-competitive manner and inhibited cytokine signaling evoked by IL-2, IL-6, IL-23, granulocyte/macrophage colony-stimulating factor, and IFN-α. JTE-052 inhibited the activation of inflammatory cells, such as T cells, B cells, monocytes, and mast cells, in vitro. Oral dosing of JTE-052 resulted in potent suppression of the IL-2-induced IFN-γ production in mice with an ED50 value of 0.24 mg/kg, which was more potent than that of tofacitinib (ED50 = 1.1 mg/kg). In the collagen-induced arthritis model, JTE-052 ameliorated articular inflammation and joint destruction even in therapeutic treatments where methotrexate was ineffective.


CONCLUSIONS
The present results indicate that JTE-052 is a highly potent JAK inhibitor, and represents a candidate anti-inflammatory agent for suppressing various types of inflammation.
Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka, 569-1125, Japan, atsuo.tanimoto@jt.com.
Atsuo
A
Tanimoto
Yoshihiro
Y
Ogawa
Chika
C
Oki
Yukari
Y
Kimoto
Keisuke
K
Nozawa
Wataru
W
Amano
Satoru
S
Noji
Makoto
M
Shiozaki
Akira
A
Matsuo
Yuichi
Y
Shinozaki
Mutsuyoshi
M
Matsushita
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D018501:Antirheumatic Agents / Q000627:therapeutic use; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D001402:B-Lymphocytes / Q000187:drug effects / Q000473:pathology; D002478:Cells, Cultured; D003094:Collagen / Q000009:adverse effects; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D066298:In Vitro Techniques; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000009:adverse effects; D053612:Janus Kinases / Q000037:antagonists & inhibitors*; D008407:Mast Cells / Q000187:drug effects / Q000473:pathology; D008727:Methotrexate / Q000627:therapeutic use; D051379:Mice; D008811:Mice, Inbred DBA; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D051381:Rats; D011917:Rats, Inbred Lew; D015398:Signal Transduction / Q000187:drug effects*; D013601:T-Lymphocytes / Q000187:drug effects / Q000473:pathology
D000893:Anti-Inflammatory Agents; D018501:Antirheumatic Agents; D016207:Cytokines; D007376:Interleukin-2; D047428:Protein Kinase Inhibitors; D007371:Interferon-gamma; D003094:Collagen; D053612:Janus Kinases; D008727:Methotrexate