Small molecule allosteric inhibitors of RORγt block Th17-dependent inflammation and associated gene expression in vivo Article Swipe
Steven A. Saenz
,
Andrea Local
,
Tiffany Carr
,
Arvind Shakya
,
Shivsmriti Koul
,
Haiqing Hu
,
Lisa Chourb
,
Justin Stedman
,
Jenna Malley
,
Laura Akullian D’Agostino
,
Veerabahu Shanmugasundaram
,
John Malona
,
Christian Schwartz
,
Lisa Beebe
,
Meghan Clements
,
Ganesh Rajaraman
,
John Y. N. Cho
,
Lan Jiang
,
Alex Dubrovskiy
,
Matthew M. Kreilein
,
Roman Shimanovich
,
Lawrence G. Hamann
,
Laure Escoubet
,
J. Michael Ellis
·
YOU?
·
· 2021
· Open Access
·
YOU?
·
· 2021
· Open Access
·
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.
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Metadata
- Type
- article
- Language
- en
- Landing Page
- https://doaj.org/article/c77d178e9fdf4a27bb6fc2263243c22d
- OA Status
- green
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W4287494310
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
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https://openalex.org/W4287494310Canonical identifier for this work in OpenAlex
- Title
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Small molecule allosteric inhibitors of RORγt block Th17-dependent inflammation and associated gene expression in vivoWork title
- Type
-
articleOpenAlex work type
- Language
-
enPrimary language
- Publication year
-
2021Year of publication
- Publication date
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2021-01-01Full publication date if available
- Authors
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Steven A. Saenz, Andrea Local, Tiffany Carr, Arvind Shakya, Shivsmriti Koul, Haiqing Hu, Lisa Chourb, Justin Stedman, Jenna Malley, Laura Akullian D’Agostino, Veerabahu Shanmugasundaram, John Malona, Christian Schwartz, Lisa Beebe, Meghan Clements, Ganesh Rajaraman, John Y. N. Cho, Lan Jiang, Alex Dubrovskiy, Matthew M. Kreilein, Roman Shimanovich, Lawrence G. Hamann, Laure Escoubet, J. Michael EllisList of authors in order
- Landing page
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https://doaj.org/article/c77d178e9fdf4a27bb6fc2263243c22dPublisher landing page
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YesWhether a free full text is available
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-
greenOpen access status per OpenAlex
- OA URL
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https://doaj.org/article/c77d178e9fdf4a27bb6fc2263243c22dDirect OA link when available
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Allosteric regulation, In vivo, Inflammation, Gene expression, Gene, Block (permutation group theory), Chemistry, Pharmacology, Cell biology, Biology, Enzyme, Biochemistry, Genetics, Immunology, Mathematics, GeometryTop concepts (fields/topics) attached by OpenAlex
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0Total citation count in OpenAlex
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10Other works algorithmically related by OpenAlex
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