Discovery of a novel RORγ antagonist with skin-restricted exposure for topical treatment of mild to moderate psoriasis

作者：Suxing Liu, Dong Liu, Ru Shen, Di Li, Qiyue Hu, Yinfa Yan, Jiakang Sun, Fengqi Zhang, Hong Wan, Ping Dong, Jun Feng, Rumin Zhang, Jing Li, Lianshan Zhang, Weikang Tao · 发表于：Scientific Reports · 年份：2021 · DOI：10.1038/s41598-021-88492-1 · 被引用次数：25 · 研究领域：Psoriasis: Treatment and Pathogenesis、Asthma and respiratory diseases、Dermatology and Skin Diseases

Clinical success of IL-17/IL-23 pathway biologics for the treatment of moderate to severe psoriasis suggests that targeting RORγt, a master regulator for the proliferation and function of Th17 cells, could be an effective alternative. However, oral RORγ antagonists (VTP43742, TAK828) with high systemic exposure showed toxicity in phase I/II clinical trials and terminated development. To alleviate the potential safety concerns, identifying compounds with skin-restricted exposure amenable for topical use is of great interest. Systematic structure activity relationship study and multi-parameter optimization led to the discovery of a novel RORγ antagonist (SHR168442) with desired properties for a topical drug. It suppressed the transcription of IL-17 gene, leading to reduction of IL-17 cytokine secretion. It showed high exposure in skin, but low in plasma. Topical application of SHR168442 in Vaseline exhibited excellent efficacy in the imiquimod-induced and IL-23-induced psoriasis-like skin inflammation mouse models and correlated with the reduction of Th17 pathway cytokines, IL-6, TNFα and IL-17A. This work demonstrated restricted skin exposure of RORγ antagonist may provide a new topical treatment option as targeted therapeutics for mild to moderate psoriasis patients and may be suitable for the treatment of any other inflammatory disorders that are accessible locally.