Novel RNA polymerase I inhibitor CX‐5461 suppresses imiquimod‐induced experimental psoriasis

Abstract Clinical treatment of psoriasis remains challenging because of possible long‐term drug toxicities and loss of therapeutic effects over time. CX‐5461 is a novel selective inhibitor of RNA polymerase I. Our previous studies have shown that CX‐5461 has potent anti‐inflammatory effects. Here we investigated whether CX‐5461 could inhibit the development of imiquimod‐induced experimental psoriasis in mice. Adult male C57BL/6 mice were used, and psoriasis‐like lesions were induced by topical imiquimod treatment. In vivo, we demonstrated that topical application of CX‐5461 prevented the development of imiquimod‐induced psoriasis, with decreases in keratinocyte proliferation, T‐cell infiltration and pathological angiogenesis. CX‐5461 also reversed existing skin inflammation induced imiquimod and retarded the development of 12‐ O ‐tetradecanoylphorbol‐13‐acetate‐induced epidermal hyperplasia and inflammation. In vitro, CX‐5461 induced cell cycle arrest in keratinocytes, inhibited expressions of interleukin‐17, interleukin‐23 receptor and retinoic acid receptor‐related orphan receptor‐γt in activated T cells, and reduced angiogenic functions of endothelial cells. In conclusion, CX‐5461 exhibits therapeutic effects on experimental psoriasis in mice, likely via multiple mechanisms including anti‐proliferative, anti‐inflammatory and anti‐angiogenic activities.