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

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 h...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/778a56f614ee48949e2ce625b054df42
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:778a56f614ee48949e2ce625b054df42
record_format	dspace
spelling	oai:doaj.org-article:778a56f614ee48949e2ce625b054df422021-12-02T16:55:25ZDiscovery of a novel RORγ antagonist with skin-restricted exposure for topical treatment of mild to moderate psoriasis10.1038/s41598-021-88492-12045-2322https://doaj.org/article/778a56f614ee48949e2ce625b054df422021-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-88492-1https://doaj.org/toc/2045-2322Abstract 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.Suxing LiuDong LiuRu ShenDi LiQiyue HuYinfa YanJiakang SunFengqi ZhangHong WanPing DongJun FengRumin ZhangJing LiLianshan ZhangWeikang TaoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q 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 Discovery of a novel RORγ antagonist with skin-restricted exposure for topical treatment of mild to moderate psoriasis
description	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.
format	article
author	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
author_facet	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
author_sort	Suxing Liu
title	Discovery of a novel RORγ antagonist with skin-restricted exposure for topical treatment of mild to moderate psoriasis
title_short	Discovery of a novel RORγ antagonist with skin-restricted exposure for topical treatment of mild to moderate psoriasis
title_full	Discovery of a novel RORγ antagonist with skin-restricted exposure for topical treatment of mild to moderate psoriasis
title_fullStr	Discovery of a novel RORγ antagonist with skin-restricted exposure for topical treatment of mild to moderate psoriasis
title_full_unstemmed	Discovery of a novel RORγ antagonist with skin-restricted exposure for topical treatment of mild to moderate psoriasis
title_sort	discovery of a novel rorγ antagonist with skin-restricted exposure for topical treatment of mild to moderate psoriasis
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/778a56f614ee48949e2ce625b054df42
work_keys_str_mv	AT suxingliu discoveryofanovelrorgantagonistwithskinrestrictedexposurefortopicaltreatmentofmildtomoderatepsoriasis AT dongliu discoveryofanovelrorgantagonistwithskinrestrictedexposurefortopicaltreatmentofmildtomoderatepsoriasis AT rushen discoveryofanovelrorgantagonistwithskinrestrictedexposurefortopicaltreatmentofmildtomoderatepsoriasis AT dili discoveryofanovelrorgantagonistwithskinrestrictedexposurefortopicaltreatmentofmildtomoderatepsoriasis AT qiyuehu discoveryofanovelrorgantagonistwithskinrestrictedexposurefortopicaltreatmentofmildtomoderatepsoriasis AT yinfayan discoveryofanovelrorgantagonistwithskinrestrictedexposurefortopicaltreatmentofmildtomoderatepsoriasis AT jiakangsun discoveryofanovelrorgantagonistwithskinrestrictedexposurefortopicaltreatmentofmildtomoderatepsoriasis AT fengqizhang discoveryofanovelrorgantagonistwithskinrestrictedexposurefortopicaltreatmentofmildtomoderatepsoriasis AT hongwan discoveryofanovelrorgantagonistwithskinrestrictedexposurefortopicaltreatmentofmildtomoderatepsoriasis AT pingdong discoveryofanovelrorgantagonistwithskinrestrictedexposurefortopicaltreatmentofmildtomoderatepsoriasis AT junfeng discoveryofanovelrorgantagonistwithskinrestrictedexposurefortopicaltreatmentofmildtomoderatepsoriasis AT ruminzhang discoveryofanovelrorgantagonistwithskinrestrictedexposurefortopicaltreatmentofmildtomoderatepsoriasis AT jingli discoveryofanovelrorgantagonistwithskinrestrictedexposurefortopicaltreatmentofmildtomoderatepsoriasis AT lianshanzhang discoveryofanovelrorgantagonistwithskinrestrictedexposurefortopicaltreatmentofmildtomoderatepsoriasis AT weikangtao discoveryofanovelrorgantagonistwithskinrestrictedexposurefortopicaltreatmentofmildtomoderatepsoriasis
_version_	1718382867153682432

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

Ejemplares similares