Discovery of Janus Kinase and Histone Deacetylase Dual Inhibitors as a New Strategy to Treat Psoriasis

Psoriasis
is a common, chronic, recurrent, and inflammatory skin
disease, which causes physical and psychological problems in patients
and lacks effective and economic therapeutics. Herein, we designed
Janus kinase (JAK) and histone deacetylase (HDAC) dual inhibitors
as a new strategy for the treatment of psoriasis. In particular, compound 11i was identified with excellent inhibitory activity toward
JAKs (JAK2 IC50 = 0.49 nM) and HDACs (HDAC6 IC50 = 12 nM). Moreover, it exhibited potent activities in inhibiting
the proliferation of TNF-α-induced HaCAT cells and the production
of nitric oxide. Importantly, compound 11i significantly
ameliorated psoriasis-like skin lesions in an imiquimod-induced murine
model with low toxicity, which was superior to JAK inhibitor momelotinib,
HDAC inhibitor vorinostat, and their combination. This work provided
a proof-of-concept for JAK/HDAC dual inhibitors as a promising strategy
for the treatment of psoriasis.