Background:

Janex-1 is an ATP-competitive and specific inhibitor of JAK3 with IC50 value of 78 μM [1].

Janus kinase 3 (JAK3) is a tyrosine kinase which belongs to the Janus kinase family. It is associated with the type I cytokine receptors that use common gamma chain, and provides enzymatic activity to the receptor. When ligands bind to the receptor, the conformational change of the receptor will activate the JAK3 and thus initiate downstream signaling. JAK3 interacts with actin-binding protein villin, and subsequently promote cytoskeletal remodeling and mucosal wound repair.

When tested with human lymphoblastoid B-cell line, Janex-1 showed significant inhibitory effect on JAK3 activity, but do not affect other types of tyrosine kinases, including Janus family tyrosine kinase JAK1 and JAK2, the ZAP/SYK family tyrosine kinase SYK, the TEC family tyrosine kinase BTK, the SRC family tyrosine kinase LYN. It suggested Janex-1 was highly specific to JAK3 inhibition [1]. Pretreated mouse islet with Janex-1 showed resistance to cytokine toxicity, i.e. the decreased NO synthase (iNOS) expression and thereby the nitric oxide (NO) production and subsequent islet damage. The molecular mechanism was considered that Janex-1 inhibit iNOS expression via inhibit JAK3 and other signaling transduction [2].

In NOD mouse model of type 1 diabetes, 60% of control mice became diabetic after 25 weeks. However, injection of Janex-1 (100 mg/kg/day) from week 10 to week 25 resulted in only 9% mice became diabetic. Because type 1 diabetes was caused by JAK3 and downstream signaling, the suppression of diabetes onset suggested the inhibition of JAK3 by Janex-1 [3].

参考文献:
[1] Sudbeck E A et al. , Structure-based Design of Specific Inhibitors of Janus Kinase 3 as Apoptosis-inducing Antileukemic Agents. Clinical cancer research. 2007, 5: 1569-1582.
[2] Lv N et al. , JANEX-1, a JAK3 inhibitor, protects pancreatic islets from cytokine toxicity through downregulation of NF-|êB activation and the JAK/STAT pathway. Experimental cell research. 2009, 315 (12): 2064-2071.
[3] Cetkovic-Cvrlje M et al. , Targeting JAK3 with JANEX-1 for prevention of autoimmune type 1 diabetes in NOD mice. Clinical immunology. 2003, 106: 213-225.