Small molecule allosteric inhibitors of RORγt block Th17-dependent inflammation and associated gene expression in vivo.
Retinoic acid receptor-related orphan nuclear receptor (ROR) γt is a member of the RORC nuclear hormone receptor family of transcription factors. RORγt functions as a critical regulator of thymopoiesis and immune responses. RORγt is expressed in multiple immune cell populations including Th17 cells,...
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Public Library of Science (PLoS)
2021
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oai:doaj.org-article:56f95d2f88a74dbfab93005fd298c8a62021-12-02T20:07:43ZSmall molecule allosteric inhibitors of RORγt block Th17-dependent inflammation and associated gene expression in vivo.1932-620310.1371/journal.pone.0248034https://doaj.org/article/56f95d2f88a74dbfab93005fd298c8a62021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0248034https://doaj.org/toc/1932-6203Retinoic acid receptor-related orphan nuclear receptor (ROR) γt is a member of the RORC nuclear hormone receptor family of transcription factors. RORγt functions as a critical regulator of thymopoiesis and immune responses. RORγt is expressed in multiple immune cell populations including Th17 cells, where its primary function is regulation of immune responses to bacteria and fungi through IL-17A production. However, excessive IL-17A production has been linked to numerous autoimmune diseases. Moreover, Th17 cells have been shown to elicit both pro- and anti-tumor effects. Thus, modulation of the RORγt/IL-17A axis may represent an attractive therapeutic target for the treatment of autoimmune disorders and some cancers. Herein we report the design, synthesis and characterization of three selective allosteric RORγt inhibitors in preclinical models of inflammation and tumor growth. We demonstrate that these compounds can inhibit Th17 differentiation and maintenance in vitro and Th17-dependent inflammation and associated gene expression in vivo, in a dose-dependent manner. Finally, RORγt inhibitors were assessed for efficacy against tumor formation. While, RORγt inhibitors were shown to inhibit tumor formation in pancreatic ductal adenocarcinoma (PDAC) organoids in vitro and modulate RORγt target genes in vivo, this activity was not sufficient to delay tumor volume in a KP/C human tumor mouse model of pancreatic cancer.Steven A SaenzAndrea LocalTiffany CarrArvind ShakyaShivsmriti KoulHaiqing HuLisa ChourbJustin StedmanJenna MalleyLaura Akullian D'AgostinoVeerabahu ShanmugasundaramJohn MalonaC Eric SchwartzLisa BeebeMeghan ClementsGanesh RajaramanJohn ChoLan JiangAlex DubrovskiyMatt KreileinRoman ShimanovichLawrence G HamannLaure EscoubetJ Michael EllisPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 11, p e0248034 (2021) |
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Medicine R Science Q Steven A Saenz Andrea Local Tiffany Carr Arvind Shakya Shivsmriti Koul Haiqing Hu Lisa Chourb Justin Stedman Jenna Malley Laura Akullian D'Agostino Veerabahu Shanmugasundaram John Malona C Eric Schwartz Lisa Beebe Meghan Clements Ganesh Rajaraman John Cho Lan Jiang Alex Dubrovskiy Matt Kreilein Roman Shimanovich Lawrence G Hamann Laure Escoubet J Michael Ellis Small molecule allosteric inhibitors of RORγt block Th17-dependent inflammation and associated gene expression in vivo. |
| description |
Retinoic acid receptor-related orphan nuclear receptor (ROR) γt is a member of the RORC nuclear hormone receptor family of transcription factors. RORγt functions as a critical regulator of thymopoiesis and immune responses. RORγt is expressed in multiple immune cell populations including Th17 cells, where its primary function is regulation of immune responses to bacteria and fungi through IL-17A production. However, excessive IL-17A production has been linked to numerous autoimmune diseases. Moreover, Th17 cells have been shown to elicit both pro- and anti-tumor effects. Thus, modulation of the RORγt/IL-17A axis may represent an attractive therapeutic target for the treatment of autoimmune disorders and some cancers. Herein we report the design, synthesis and characterization of three selective allosteric RORγt inhibitors in preclinical models of inflammation and tumor growth. We demonstrate that these compounds can inhibit Th17 differentiation and maintenance in vitro and Th17-dependent inflammation and associated gene expression in vivo, in a dose-dependent manner. Finally, RORγt inhibitors were assessed for efficacy against tumor formation. While, RORγt inhibitors were shown to inhibit tumor formation in pancreatic ductal adenocarcinoma (PDAC) organoids in vitro and modulate RORγt target genes in vivo, this activity was not sufficient to delay tumor volume in a KP/C human tumor mouse model of pancreatic cancer. |
| format |
article |
| author |
Steven A Saenz Andrea Local Tiffany Carr Arvind Shakya Shivsmriti Koul Haiqing Hu Lisa Chourb Justin Stedman Jenna Malley Laura Akullian D'Agostino Veerabahu Shanmugasundaram John Malona C Eric Schwartz Lisa Beebe Meghan Clements Ganesh Rajaraman John Cho Lan Jiang Alex Dubrovskiy Matt Kreilein Roman Shimanovich Lawrence G Hamann Laure Escoubet J Michael Ellis |
| author_facet |
Steven A Saenz Andrea Local Tiffany Carr Arvind Shakya Shivsmriti Koul Haiqing Hu Lisa Chourb Justin Stedman Jenna Malley Laura Akullian D'Agostino Veerabahu Shanmugasundaram John Malona C Eric Schwartz Lisa Beebe Meghan Clements Ganesh Rajaraman John Cho Lan Jiang Alex Dubrovskiy Matt Kreilein Roman Shimanovich Lawrence G Hamann Laure Escoubet J Michael Ellis |
| author_sort |
Steven A Saenz |
| title |
Small molecule allosteric inhibitors of RORγt block Th17-dependent inflammation and associated gene expression in vivo. |
| title_short |
Small molecule allosteric inhibitors of RORγt block Th17-dependent inflammation and associated gene expression in vivo. |
| title_full |
Small molecule allosteric inhibitors of RORγt block Th17-dependent inflammation and associated gene expression in vivo. |
| title_fullStr |
Small molecule allosteric inhibitors of RORγt block Th17-dependent inflammation and associated gene expression in vivo. |
| title_full_unstemmed |
Small molecule allosteric inhibitors of RORγt block Th17-dependent inflammation and associated gene expression in vivo. |
| title_sort |
small molecule allosteric inhibitors of rorγt block th17-dependent inflammation and associated gene expression in vivo. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2021 |
| url |
https://doaj.org/article/56f95d2f88a74dbfab93005fd298c8a6 |
| work_keys_str_mv |
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| _version_ |
1718375240239677440 |