Design, Synthesis, and Biological Evaluation of Janus Kinase (JAK) and Histone Deacetylase (HDAC) Dual Inhibitors for the Treatment of Psoriasis

Psoriasis is a chronic, immune-mediated inflammatory dermatosis featured by aberrant keratinocyte hyperproliferation and persistent cutaneous inflammatory infiltration, lacking curative small-molecule therapeutics. Dysregulated Janus kinase signal transducer and activator of transcription pathway (JAK/STAT) and histone deacetylase (HDAC)-dependent epigenetic signaling represented essential pathogenic axes driving psoriasis progression. Inspired by synergistic crosstalk between these two pathways and our previous work identifying anti-psoriatic JAK/HDAC dual inhibitors, a series of novel dual JAK/HDAC inhibitors were rationally designed and synthesized. Systematic enzymatic profiling revealed compound 11e exerted potent and balanced JAK2 and HDAC6 inhibitory activity (JAK2 IC50 = 2.1 nM, HDAC6 IC50 = 3.1 nM). Critically, topical cream formulation and oral administration of 11e dramatically alleviated erythema, scaling, and epidermal hyperplasia in the imiquimod-induced psoriasis mouse model. Collectively, compound 11e served as a promising lead compound for anti-psoriasis drug development, providing validated structural scaffolds for further optimization of next-generation JAK/HDAC dual inhibitors.