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

Saenz, S. A.; Local, A.; Carr, T.; Shakya, A.; Koul, S.; Hu, H.; Chourb, L.; Stedman, J.; Malley, J.; DAgostino, L. A.; Shanmugasundaram, V.; Malona, J.; Schwartz, C. E.; Beebe, L.; Clements, M.; Rajaraman, G.; Cho, J.; Jiang, L.; Dubrovskiy, A.; Kreilein, M.; Shimanovich, R.; Hamann, L. G.; Escoubet, L.; Ellis, J. M.

doi:10.1101/2021.02.19.431952

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bioRxiv · 10.1101/2021.02.19.431952

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

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Abstract

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 shown to inhibit tumor formation in pancreatic ductal adenocarcinoma (PDAC) organoids.

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Saenz, S. A., Local, A., Carr, T., Shakya, A., Koul, S., Hu, H., Chourb, L., Stedman, J., Malley, J., DAgostino, L. A., Shanmugasundaram, V., Malona, J., Schwartz, C. E., Beebe, L., Clements, M., Rajaraman, G., Cho, J., Jiang, L., Dubrovskiy, A., Kreilein, M., Shimanovich, R., Hamann, L. G., Escoubet, L., Ellis, J. M.. 2021-02-19. Small molecule allosteric inhibitors of RORγt block Th17-dependent inflammation and associated gene expression in vivo.. https://doi.org/10.1101/2021.02.19.431952

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