The Janus kinase and Signal Transducer and Activator of Transcription protein (JAK/STAT) pathway is known to be involved in inflammatory and neoplastic skin diseases, like psoriasis, atopic dermatitis, alopecia areata, vitiligo and melanoma. JAKs, a small family of kinases - JAK1, JAK2, JAK3 and Tyrosine Kinase 2 (TYK2), bind directly to the intracellular domains of Type I/II cytokine receptors and not to other classes of cytokine receptors. JAKs are located at the cytoplasmic tail of various cytokine receptors, and are activated upon receptor-ligand interaction. Due to the kinase activity, JAK activation results in auto-phosphorylation as well as phosphorylation of the cytokine receptor chains, and the combination of JAKs and the receptor form specific binding sites for one or more members of the STAT [signal transducer and activator of transcription] family. GSK2586184 (Solcitinib) is an orally active, competitive, potent, selective JAK1 inhibitor. In biochemical phosphorylation assays, GSK2586184 has an IC 50 of 9.8 nM, and shows 11-, 55- and 23-fold selectivity over JAK2, JAK3 and TYK2, respectively[2]. GSK2586184 was administered in two patients 400 mg twice daily for 48 days with moderate-to-severe ulcerative colitis (UC). The result showed that the JAK1 selective inhibitor GSK2586184 was well tolerated and induced clinical and endoscopic response in two patients with moderate-to-severe UC. GSK2586184, a Janus kinase 1 selective inhibitor, induced clinical and endoscopic response in ulcerative colitis, however, the study was discontinued at an early stage due to liver toxicity observed in systemic lupus patients receiving the drug[3].
作用机制
A ring nitrogen and the hydrogen associated with the adjacent exocyclic amine are involved in binding to the hinge region of the JAK1 kinase. This places the conserved cyclopropyl group in a lipophilic pocket.
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