Cytokines play an important role in cell growth, differentiation, and function in many cell types. They bind to cell surface receptors and then trigger the down-stream signal. As a result, they also can result in the activation of the Janus kinase family of tyrosine kinases.
Janus kinase (JAK) is a family of tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway. JAK family includes Jak1, Jak2, Jak3, and Tyk2. Jak3 is mainly found4 in lymphoid cells and appears only to be stimulated by activation of cytokine receptors, such as IL-2R, IL-4R, IL-7R, IL-11R, and IL-13R, but not by T cell receptor activation.
ZM 449829 is a selective and ATP competitive inhibitor of JAK3, with a pIC50 of 6.8. It is also a very weak inhibitor of EGF-R (pIC50=5.0), Jak1 (pIC50=4.7). In YTS, NK92, and ex vivo NK cells, ZM449829 blocks IL-2-induced STAT5 phosphorylation and inhibits the phosphorylation of STAT5.
Increased intraocular pressure (IOP) is one of the factors for primary open-angle glaucoma (POAG). Obstruction to aqueous humor (AH) outflow at the trabecular meshwork (TM) in the eye is the main reason for IOP. Downregulation of TGM2 can significantly reduce TGFβ-induced ocular hypertension. ZM 449829 binds to TGM2 and inhibits crosslinking activity by locking it in an inactive state. In primary human glaucomatous cells, ZM 449829 reduces the fibronectin deposition.
ZM39923 potently inhibits tissue transglutaminase (TGM2) with an IC50 of 10 nM. Besides, it acts directly on purified TGM2 to inhibit the Ca2+ activated form of TGM2.
In vivo, in c57 mice, ZM 449829 once daily helps to maintain the gross morphology of the eye, and cornea looked normal. IOP measurements also do not exhibit any aberrant changes. As a result, TGM2 is a potential therapeutic target for glaucoma.
In conclusion, ZM39923 is a potent JAK3 inhibitor and also inhibits TGM2 activity.