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,...
Guardado en:
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , |
---|---|
Formato: | article |
Lenguaje: | EN |
Publicado: |
Public Library of Science (PLoS)
2021
|
Materias: | |
Acceso en línea: | https://doaj.org/article/c77d178e9fdf4a27bb6fc2263243c22d |
Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
id |
oai:doaj.org-article:c77d178e9fdf4a27bb6fc2263243c22d |
---|---|
record_format |
dspace |
spelling |
oai:doaj.org-article:c77d178e9fdf4a27bb6fc2263243c22d2021-11-18T06:34:40ZSmall molecule allosteric inhibitors of RORγt block Th17-dependent inflammation and associated gene expression in vivo1932-6203https://doaj.org/article/c77d178e9fdf4a27bb6fc2263243c22d2021-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8577775/?tool=EBIhttps://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 (2021) |
institution |
DOAJ |
collection |
DOAJ |
language |
EN |
topic |
Medicine R Science Q |
spellingShingle |
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/c77d178e9fdf4a27bb6fc2263243c22d |
work_keys_str_mv |
AT stevenasaenz smallmoleculeallostericinhibitorsofrorgtblockth17dependentinflammationandassociatedgeneexpressioninvivo AT andrealocal smallmoleculeallostericinhibitorsofrorgtblockth17dependentinflammationandassociatedgeneexpressioninvivo AT tiffanycarr smallmoleculeallostericinhibitorsofrorgtblockth17dependentinflammationandassociatedgeneexpressioninvivo AT arvindshakya smallmoleculeallostericinhibitorsofrorgtblockth17dependentinflammationandassociatedgeneexpressioninvivo AT shivsmritikoul smallmoleculeallostericinhibitorsofrorgtblockth17dependentinflammationandassociatedgeneexpressioninvivo AT haiqinghu smallmoleculeallostericinhibitorsofrorgtblockth17dependentinflammationandassociatedgeneexpressioninvivo AT lisachourb smallmoleculeallostericinhibitorsofrorgtblockth17dependentinflammationandassociatedgeneexpressioninvivo AT justinstedman smallmoleculeallostericinhibitorsofrorgtblockth17dependentinflammationandassociatedgeneexpressioninvivo AT jennamalley smallmoleculeallostericinhibitorsofrorgtblockth17dependentinflammationandassociatedgeneexpressioninvivo AT lauraakulliandagostino smallmoleculeallostericinhibitorsofrorgtblockth17dependentinflammationandassociatedgeneexpressioninvivo AT veerabahushanmugasundaram smallmoleculeallostericinhibitorsofrorgtblockth17dependentinflammationandassociatedgeneexpressioninvivo AT johnmalona smallmoleculeallostericinhibitorsofrorgtblockth17dependentinflammationandassociatedgeneexpressioninvivo AT cericschwartz smallmoleculeallostericinhibitorsofrorgtblockth17dependentinflammationandassociatedgeneexpressioninvivo AT lisabeebe smallmoleculeallostericinhibitorsofrorgtblockth17dependentinflammationandassociatedgeneexpressioninvivo AT meghanclements smallmoleculeallostericinhibitorsofrorgtblockth17dependentinflammationandassociatedgeneexpressioninvivo AT ganeshrajaraman smallmoleculeallostericinhibitorsofrorgtblockth17dependentinflammationandassociatedgeneexpressioninvivo AT johncho smallmoleculeallostericinhibitorsofrorgtblockth17dependentinflammationandassociatedgeneexpressioninvivo AT lanjiang smallmoleculeallostericinhibitorsofrorgtblockth17dependentinflammationandassociatedgeneexpressioninvivo AT alexdubrovskiy smallmoleculeallostericinhibitorsofrorgtblockth17dependentinflammationandassociatedgeneexpressioninvivo AT mattkreilein smallmoleculeallostericinhibitorsofrorgtblockth17dependentinflammationandassociatedgeneexpressioninvivo AT romanshimanovich smallmoleculeallostericinhibitorsofrorgtblockth17dependentinflammationandassociatedgeneexpressioninvivo AT lawrenceghamann smallmoleculeallostericinhibitorsofrorgtblockth17dependentinflammationandassociatedgeneexpressioninvivo AT laureescoubet smallmoleculeallostericinhibitorsofrorgtblockth17dependentinflammationandassociatedgeneexpressioninvivo AT jmichaelellis smallmoleculeallostericinhibitorsofrorgtblockth17dependentinflammationandassociatedgeneexpressioninvivo |
_version_ |
1718424505880150016 |