SHR0302 is an Orally Active and Selective JAK1 Inhibitor

SHR0302 is an Orally Active and Selective JAK1 Inhibitor

Rheumatoid arthritis (RA) is a kind of destructive systemic autoimmune disease. Many different inflammatory cells invade the joint synovium. In addition, the destruction of cartilage and bone is due to the hyperplasia of the fibroblast-like synoviocytes (FLS). Many inflammatory mediators are responsible for joint-inflammation and destruction.

JAK inhibition in RA plays an important role. Such as tofacitinib, an orally active JAK inhibitor, it can decrease T-cell activation, pro-inflammatory cytokine production. The IC50 of SHR0302 for JAK1 is lower than that of tofacitinib, however, researches of SHR0302 is still on the way.

SHR0302 is an Orally Active and Selective JAK1 Inhibitor 2020 06 05 - SHR0302 is an Orally Active and Selective JAK1 Inhibitor

In this article, we will introduce SHR0302 in vitro and in vivo.

SHR0302 is a potent and orally active all members of the JAK family inhibitor, particularly JAK1. The selectivity of SHR0302 for JAK1 is >10-fold for JAK2, 77-fold for JAK3, 420-fold for Tyk2. It inhibits JAK1-STAT3 phosphorylation and induces the apoptosis of hepatic stellate cells. SHR0302 has an anti-proliferative and anti-inflammatory effect.
Firstly, in Hepatic stellate cells (HSCs), SHR0302 treatment displays an inhibitory effect on the proliferation of HSCs in a concentration-dependent manner. At the same time, it exerts an inhibitory effect on the activation, proliferation, and migration of HSCs. Additionally, SHR0302 treatment induces the apoptosis of HSCs in a dose-dependent manner. SHR0302 treatment significantly increases the activation of caspase-3 and Bax in HSCs and decreases the expression of Bcl-2. It also inhibits the activation of the Akt signaling pathway.

In Vivo, in Male Sprague-Dawley (SD) rats (150-180 g) injected with complete Freund’s adjuvant (CFA). SHR0302 treatment suppresses the severity of AA rats by attenuating the arthritis index, arthritis global assessment, and paw swelling degree. it also alleviates histopathology of the spleen and joint of AA rats.
SHR0302 can inhibit the proliferation of T, B, and fibroblast-like synoviocytes (FLS). besides, it down-regulates cytokines TNF-α, IL-1β, IL-17, and antibody IgG1, IgG2a levels, and suppresses the proportion of Th17 and total B, and inhibits JAK1-STAT3 phosphorylation.

In conclusion, SHR0302  is a promising JAK inhibitor and can be used for the study of  Rheumatoid arthritis.

Reference:

Huaxun Wu, et al. Joint Bone Spine. 2016 Oct;83(5):525-32.

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