Facile skin targeting of a thalidomide analog containing benzyl chloride moiety alleviates experimental psoriasis via the suppression of MAPK/NF-κB/AP-1 phosphorylation in keratinocytes

•A thalidomide derivative was assessed for its anti-inflammatory activity.•The derivative suppressed cytokine expression to a greater degree than thalidomide.•The derivative penetrated skin due to its feasible lipophilicity and small size.•This compound regulated inflammation via inhibition of MAPKs/NF-κB/AP-1 signaling.•Thalidomide analog has potential as a therapeutic agent against psoriasis. Thalidomide can be a TNF-α inhibitor for treating skin inflammation. This drug exhibits a strong toxicity that limits its application. We synthesized a thalidomide analog containing the benzyl chloride group (2-[1-(3-chlorobenzyl)-2,6-dioxopiperidin-3-yl]isoindoline-1,3-dione, CDI) to examine anti-inflammatory activity against psoriasis. The evaluation was conducted by the experimental platforms of in vitro TNF-α- or imiquimod (IMQ)-stimulated HaCaT cells and in vivo IMQ-induced psoriasiform plaque. Using the in vitro keratinocyte model, we demonstrated a greater inhibition of IL-1β, IL-6, and IL-24 by CDI than by thalidomide. No significant cytotoxicity was observed at 100 μM. CDI delivered facilely into the skin with a cutaneous targeting ability 228-fold greater than thalidomide. CDI caused a negligible irritation on healthy mouse skin. We showed that topically applied CDI reduced IMQ-induced red scaly lesions, hyperplasia, microabscesses, and cytokine expression in the mouse model. The skin-barrier function measured by transepidermal water loss (TEWL) could be partially recovered from 50.6–36.3 g/m2/h by CDI. The mechanistic study showed that CDI suppressed cytokine production by inhibiting the phosphorylation of NF-κB and AP-1 via MAPK pathways. CDI would be beneficial for the development of a therapeutic agent against psoriasis.