Academic Journal
Discovery of a highly selective JAK3 inhibitor for the treatment of rheumatoid arthritis
| العنوان: | Discovery of a highly selective JAK3 inhibitor for the treatment of rheumatoid arthritis |
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| المؤلفون: | Pei, Heying, He, Linhong, Shao, Mingfeng, Yang, Zhuang, Ran, Yan, Li, Dan, Zhou, Yuanyuan, Tang, Minghai, Wang, Taijin, Gong, Yanqiu, Chen, Xiaoxin, Yang, Shengyong, Xiang, Mingli, Chen, Lijuan |
| المصدر: | Scientific Reports ; volume 8, issue 1 ; ISSN 2045-2322 |
| بيانات النشر: | Springer Science and Business Media LLC |
| سنة النشر: | 2018 |
| الوصف: | Janus tyrosine kinase 3 (JAK3) is expressed in lymphoid cells and is involved in the signalling of T cell functions. The development of a selective JAK3 inhibitor has been shown to have a potential benefit in the treatment of autoimmune disorders. In this article, we developed the 4-aminopiperidine-based compound RB1 , which was highly selective for JAK3 inhibition, with an IC 50 of value of 40 nM, but did not inhibit JAK1, JAK2 or tyrosine kinase 2 (TYK2) at concentrations up to 5 µM. Furthermore, RB1 also exhibited favourable selectivity against a panel of representative kinases. In a battery of cytokine-stimulated cell-based assays, this potent inhibitor of JAK3 activity with good selectivity against other kinases could potently inhibit JAK3 activity over the activity of JAK1 or JAK2 (over at least 100-fold). A combination of liquid chromatography-mass spectrometry (LC-MS) experiments validated that RB1 covalently modified the unique cysteine 909 residue in JAK3. In vivo , RB1 exerted significantly improved pathology in the joints of a collagen-induced arthritis mouse model. The reasonable pharmacokinetics properties (F = 72.52%, T1/2 = 14.6 h) and favourable results of toxicology experiments (LD 50 > 2 g/kg) suggest that RB1 has the potential to be an efficacious treatment for RA. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| DOI: | 10.1038/s41598-018-23569-y |
| الاتاحة: | http://dx.doi.org/10.1038/s41598-018-23569-y https://www.nature.com/articles/s41598-018-23569-y.pdf https://www.nature.com/articles/s41598-018-23569-y |
| Rights: | https://creativecommons.org/licenses/by/4.0 ; https://creativecommons.org/licenses/by/4.0 |
| رقم الانضمام: | edsbas.D3A08CB4 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1038/s41598-018-23569-y |
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