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

Autor: Shivsmriti Koul, John Malona, Lisa Beebe, Laure Escoubet, Meghan Clements, Arvind Shakya, Veerabahu Shanmugasundaram, Lan Jiang, Lawrence G. Hamann, Matt M. Kreilein, Jenna Malley, C. Eric Schwartz, Roman Shimanovich, Ganesh Rajaraman, Alex Dubrovskiy, Laura Akullian D’Agostino, Justin Stedman, Andrea Local, J. Michael Ellis, Tiffany Carr, Steven A. Saenz, Haiqing Hu, John Cho, Lisa Chourb
Rok vydání: 2021
Předmět:
Carcinogenesis
Physiology
Cell
Cancer Treatment
Retinoic acid
Gene Expression
Mice
chemistry.chemical_compound
RAR-related orphan receptor gamma
Immune Physiology
Medicine and Health Sciences
Organ Cultures
Immune Response
Innate Immune System
Multidisciplinary
Interleukin-17
Nuclear Receptor Subfamily 1
Group F
Member 1
Animal Models
Organoids
medicine.anatomical_structure
Oncology
Experimental Organism Systems
Cytokines
Medicine
Biological Cultures
Anatomy
medicine.symptom
Signal Transduction
Research Article
Science
Immunology
Allosteric regulation
Mouse Models
Inflammation
Research and Analysis Methods
Pancreatic Cancer
Model Organisms
Signs and Symptoms
Immune system
In vivo
Gastrointestinal Tumors
Genetics
medicine
Animals
Transcription factor
Biology and Life Sciences
Cancers and Neoplasms
Molecular Development
Nuclear receptor
chemistry
Ears
Immune System
Animal Studies
Cancer research
Th17 Cells
Clinical Medicine
Head
Developmental Biology
Zdroj: PLoS ONE, Vol 16, Iss 11 (2021)
PLoS ONE, Vol 16, Iss 11, p e0248034 (2021)
PLoS ONE
DOI: 10.1101/2021.02.19.431952
Popis: 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.
Databáze: OpenAIRE
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