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

• Published in: PloS one Vol. 16; no. 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: Journal Article
• Language: English
• Published: United States Public Library of Science 09.11.2021; Public Library of Science (PLoS)
• Subjects: Adenocarcinoma; Allosteric properties; Animal models; Animals; Anticancer properties; Autoimmune diseases; Biology and Life Sciences; Cancer; Carcinogenesis - drug effects; Carcinogenesis - genetics; Cytokines; Disease; Gene expression; Gene Expression - drug effects; Genetic engineering; Helper cells; Immune response; Immune system; Immunology; Inflammation; Inflammation - genetics; Inflammation - metabolism; Inhibitors; Interleukin-17 - metabolism; Lymphocytes T; Medicine and Health Sciences; Mice; Nuclear Receptor Subfamily 1, Group F, Member 1 - antagonists & inhibitors; Nuclear Receptor Subfamily 1, Group F, Member 1 - metabolism; Optimization; Organoids; Pancreatic cancer; Pharmaceuticals; Psoriasis; Psoriatic arthritis; R&D; Receptors; Research & development; Research and Analysis Methods; Response rates; Retinoic acid; Signal Transduction - drug effects; Signal Transduction - genetics; Th17 Cells - drug effects; Th17 Cells - metabolism; Therapeutic targets; Thymopoiesis; Transcription factors; Tumors; California; United States > US; Massachusetts; New Jersey
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0248034

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.