Pharmacological properties of JTE-052: a novel potent JAK inhibitor that suppresses various inflammatory responses in vitro and in vivo.

Abstract

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.

• Authors: Atsuo Tanimoto, Yoshihiro Ogawa, Chika Oki, Yukari Kimoto, Keisuke Nozawa, Wataru Amano, Satoru Noji, Makoto Shiozaki, Akira Matsuo, Yuichi Shinozaki, Mutsuyoshi Matsushita
• Journal: Inflammation research : official journal of the European Histamine Research Society ... [et al.] (Inflamm Res) Vol. 64 Issue 1 Pg. 41-51 (Jan 2015) ISSN: 1420-908X [Electronic] Switzerland
• PMID: 25387665 (Publication Type: Journal Article)

Chemical References

• Anti-Inflammatory Agents
• Antirheumatic Agents
• Cytokines
• Interleukin-2
• Protein Kinase Inhibitors
• Interferon-gamma
• Collagen
• Janus Kinases
• Methotrexate

Topics

• Animals
• Anti-Inflammatory Agents (pharmacology, therapeutic use)
• Antirheumatic Agents (therapeutic use)
• Arthritis, Experimental (chemically induced, metabolism, prevention & control)
• B-Lymphocytes (drug effects, pathology)
• Cells, Cultured
• Collagen (adverse effects)
• Cytokines (metabolism)
• Disease Models, Animal
• Humans
• In Vitro Techniques
• Inflammation (chemically induced, metabolism, prevention & control)
• Interferon-gamma (metabolism)
• Interleukin-2 (adverse effects)
• Janus Kinases (antagonists & inhibitors)
• Mast Cells (drug effects, pathology)
• Methotrexate (therapeutic use)
• Mice
• Mice, Inbred DBA
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Rats
• Rats, Inbred Lew
• Signal Transduction (drug effects)
• T-Lymphocytes (drug effects, pathology)