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

Steven A Saenz,Justin Stedman,Lawrence G Hamann,Arvind Shakya,J Michael Ellis,John Malona,Lan Jiang,Laura Akullian D’Agostino,Andrea Local,Lisa Chourb,Meghan Clements,Jenna Malley,Shivsmriti Koul,Roman Shimanovich,Veerabahu Shanmugasundaram,Lisa Beebe,Ganesh Rajaraman,John Cho,Laure Escoubet,Alex Dubrovskiy,Haibing Hu ,T D Carr ,Matthew M Kreilein ,Christian Schwartz

doi:10.1371/journal.pone.0248034

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.

Highlights

Psoriasis is a chronic, immune-mediated disease characterized by the presence of large, erythematous, scaly plaques commonly found at multiple sites on the skin surface [1,2,3]
A multitude of pre-clinical data demonstrated that targeting the RORγt/IL-17A/IL-23 pathway ameliorates disease pathology in multiple autoimmune and inflammatory diseases
We report the design, synthesis and pre-clinical characterization of 3 potent, selective allosteric RORγt inhibitors (Compounds 1, 2 and 3) with structural similarity and notable differences to those previously reported by Lycera and Merck [18, 19]

Summary

Introduction

Immune-mediated disease characterized by the presence of large, erythematous, scaly plaques commonly found at multiple sites on the skin surface [1,2,3]. Elevated gene expression levels of proinflammatory cytokines including TNFα, IL-17A, IL-22 and IL-23 have been reported in skin biopsies from psoriatic patients [2,3,4]. These cytokines are known to act on various cell types within the skin tissue microenvironment, including keratinocytes, neutrophils, endothelial cells and fibroblasts which, in turn, promote aberrant keratinocyte activation, hyperproliferation and tissue inflammation. Phototherapy or systemic medications including methotrexate and cyclosporine are common, as are neutralizing monoclonal antibodies against TNFα.

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