Discovery of a novel CDK8 inhibitor as dual suppressor of NF-κB-driven inflammation and promoter of Treg differentiation for psoriasis treatment.

Abstract

Cyclin-dependent kinase 8 (CDK8) has emerged as an important regulator of inflammatory signaling and immune homeostasis, representing a promising therapeutic target for psoriasis and other immune-mediated diseases. Herein, we report the structure-based optimization of the previously reported CDK8 inhibitor to develop a series of novel derivatives. Through systematic structure-activity relationship (SAR) analysis, compound LW-1 was identified as a lead candidate with potent CDK8 inhibitory activity (IC50 = 24.5 ± 1.4 nM) and significantly improved metabolic stability. Target engagment studies confirmed that LW-1 directly binds to CDK8 with high affinity. Mechanistically, LW-1 suppressed NF-κB-dependent transcription and reduced pro-inflammatory cytokine expression, while promoting regulatory T cell (Treg) differentiation through modulation of the STAT1 and TGF-β/Smad signaling pathways. Pharmacokinetic evaluation revealed that LW-1 possessed markedly improved metabolic stability (t₁/₂ = 37.11 min in mouse liver microsome) and prolonged elimination half-life in rats (t₁/₂ = 4.8 h, po), along with acceptable oral bioavailability (F = 27.1%). In the IMQ-induced psoriasis-like mouse model, LW-1 markedly alleviated skin inflammation by promoting Treg differentiation and suppressing pro-inflammatory cytokine production. Collectively, LW-1 represents a promising CDK8 inhibitor with improved drug-like properties and potent anti-psoriatic efficacy, providing a potential therapeutic candidate for the treatment of psoriasis and other inflammatory diseases.