Dual CDK6 and CDK9 inhibitors as anti-psoriasis agents: Design, synthesis, and anti-inflammatory activity.

Skin hyperplasia and aberrant secretion of inflammatory factors are typical features of psoriasis. Given the cooperative role of CDK6-mediated cell proliferation and CDK9-mediated disturbance of inflammatory cytokines in the progression of psoriasis, dual inhibition of CDK6 and CDK9 is expected to not only exert synergetic anti-psoriatic effects but also reduce the toxicity of single-target inhibition. In this study, on the basis of our previously discovered lead, a total of 17 final compounds were designed and synthesized for exploring additional hydrogen bond interactions with hydrophilic residues in the inner pocket of CDK6 or CDK9. Among them, 4, with dual CDK6 and CDK9 inhibitory activities, was capable to ameliorate inflammation in vitro. Furthermore, it inhibited the activation of STAT3 pathway and decreased the mRNA levels of inflammatory factors in IFN-γ/TNF-α-induced HaCaT cells. These findings indicate dual CDK6 and CDK9 inhibitors may emerge as potential therapeutic agents for psoriasis.