Small molecule allosteric inhibitors of RORγt block Th17-dependent inflammation and associated gene expression in vivo.

Abstract

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.

• Authors: 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
• Journal: PloS one (PLoS One) Vol. 16 Issue 11 Pg. e0248034 ( 2021) ISSN: 1932-6203 [Electronic] United States
• PMID: 34752458 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Interleukin-17
• Nuclear Receptor Subfamily 1, Group F, Member 1
• Rora protein, mouse

Topics

• Animals
• Carcinogenesis (drug effects, genetics)
• Gene Expression (drug effects)
• Inflammation (genetics, metabolism)
• Interleukin-17 (metabolism)
• Mice
• Nuclear Receptor Subfamily 1, Group F, Member 1 (antagonists & inhibitors, metabolism)
• Signal Transduction (drug effects, genetics)
• Th17 Cells (drug effects, metabolism)