Small molecule allosteric inhibitors of RORt 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 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.