Abstract
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.
Highlights
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
Clinical success of IL-23/IL-17 pathway biologics suggests that targeting RORγt antagonists could be an effective alternative therapy for psoriasis
Based on the modeled pose of GSK805, we designed a new chemical scaffold with a benzimidazole core to mimic the amide of GSK805 while keeping the key interactions with the RORγ ligand-binding domain (LBD) such as hydrogen bonds with Cys 320, Phe 377, Gln[286], Leu[287] and Arg 367 (Fig. 1a,b)
Summary
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. Oral RORγ antagonists (VTP43742, TAK828) with high systemic exposure showed toxicity in phase I/II clinical trials and terminated development. 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. Topical corticosteroids and vitamin D analogues are applied to treat patients with mild to moderate psoriasis These treatments have limited efficacy, and cause significant side effects and patients must avoid long-term use. The skin-restricted exposure of RORγ antagonists may alleviate the safety risk due to systemic exposure while still maintaining similar efficacy as biologics in Scientific Reports | (2021) 11:9132
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