Small molecule allosteric inhibitors of ROR[gamma]t block Th17-dependent inflammation and associated gene expression in vivo

Retinoic acid receptor-related orphan nuclear receptor (ROR) [gamma]t is a member of the RORC nuclear hormone receptor family of transcription factors. ROR[gamma]t functions as a critical regulator of thymopoiesis and immune responses. ROR[gamma]t is expressed in multiple immune cell populations inc...

Full description

Saved in:
Bibliographic Details
Published in:PloS one 2021-11, Vol.16 (11), p.e0248034
Main Authors: Saenz, Steven A, Local, Andrea, Carr, Tiffany, Shakya, Arvind, Koul, Shivsmriti, Hu, Haiqing, Chourb, Lisa, Stedman, Justin, Malley, Jenna, D'Agostino, Laura Akullian, Shanmugasundaram, Veerabahu, Malona, John, Schwartz, C. Eric, Beebe, Lisa, Clements, Meghan, Rajaraman, Ganesh, Cho, John, Jiang, Lan, Dubrovskiy, Alex, Kreilein, Matt, Shimanovich, Roman, Hamann, Lawrence G, Escoubet, Laure, Ellis, J. Michael
Format: Article
Language:English
Subjects:
Analysis
Care and treatment
Development and progression
Diagnosis
Gene expression
Immune response
Psoriasis
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Retinoic acid receptor-related orphan nuclear receptor (ROR) [gamma]t is a member of the RORC nuclear hormone receptor family of transcription factors. ROR[gamma]t functions as a critical regulator of thymopoiesis and immune responses. ROR[gamma]t 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 ROR[gamma]t/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 ROR[gamma]t 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, ROR[gamma]t inhibitors were assessed for efficacy against tumor formation. While, ROR[gamma]t inhibitors were shown to inhibit tumor formation in pancreatic ductal adenocarcinoma (PDAC) organoids in vitro and modulate ROR[gamma]t target genes in vivo, this activity was not sufficient to delay tumor volume in a KP/C human tumor mouse model of pancreatic cancer.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0248034