Discovery of Janus\nKinase and Histone Deacetylase\nDual Inhibitors as a New Strategy to Treat Psoriasis

Psoriasis\nis a common, chronic, recurrent, and inflammatory skin\ndisease, which causes physical and psychological problems in patients\nand lacks effective and economic therapeutics. Herein, we designed\nJanus kinase (JAK) and histone deacetylase (HDAC) dual inhibitors\nas a new strategy for the treatment of psoriasis. In particular, compound <b>11i</b> was identified with excellent inhibitory activity toward\nJAKs (JAK2 IC<sub>50</sub> = 0.49 nM) and HDACs (HDAC6 IC<sub>50</sub> = 12 nM). Moreover, it exhibited potent activities in inhibiting\nthe proliferation of TNF-α-induced HaCAT cells and the production\nof nitric oxide. Importantly, compound <b>11i</b> significantly\nameliorated psoriasis-like skin lesions in an imiquimod-induced murine\nmodel with low toxicity, which was superior to JAK inhibitor momelotinib,\nHDAC inhibitor vorinostat, and their combination. This work provided\na proof-of-concept for JAK/HDAC dual inhibitors as a promising strategy\nfor the treatment of psoriasis.