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Current Therapeutic Landscape and Safety Roadmap for Targeting the Aryl Hydrocarbon Receptor in Inflammatory Gastrointestinal Indications

Target modulation of the AhR for inflammatory gastrointestinal (GI) conditions holds great promise but also the potential for safety liabilities both within and beyond the GI tract. The ubiquitous expression of the AhR across mammalian tissues coupled with its role in diverse signaling pathways make...

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Autores principales: Faber, Samantha C., Lahoti, Tejas S., Taylor, Ewan R., Lewis, Lauren, Sapiro, Jessica M., Toledo Sales, Vicencia, Dragan, Yvonne P., Jeffy, Brandon D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9139855/
https://www.ncbi.nlm.nih.gov/pubmed/35626744
http://dx.doi.org/10.3390/cells11101708
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author Faber, Samantha C.
Lahoti, Tejas S.
Taylor, Ewan R.
Lewis, Lauren
Sapiro, Jessica M.
Toledo Sales, Vicencia
Dragan, Yvonne P.
Jeffy, Brandon D.
author_facet Faber, Samantha C.
Lahoti, Tejas S.
Taylor, Ewan R.
Lewis, Lauren
Sapiro, Jessica M.
Toledo Sales, Vicencia
Dragan, Yvonne P.
Jeffy, Brandon D.
author_sort Faber, Samantha C.
collection PubMed
description Target modulation of the AhR for inflammatory gastrointestinal (GI) conditions holds great promise but also the potential for safety liabilities both within and beyond the GI tract. The ubiquitous expression of the AhR across mammalian tissues coupled with its role in diverse signaling pathways makes development of a “clean” AhR therapeutically challenging. Ligand promiscuity and diversity in context-specific AhR activation further complicates targeting the AhR for drug development due to limitations surrounding clinical translatability. Despite these concerns, several approaches to target the AhR have been explored such as small molecules, microbials, PROTACs, and oligonucleotide-based approaches. These various chemical modalities are not without safety liabilities and require unique de-risking strategies to parse out toxicities. Collectively, these programs can benefit from in silico and in vitro methodologies that investigate specific AhR pathway activation and have the potential to implement thresholding parameters to categorize AhR ligands as “high” or “low” risk for sustained AhR activation. Exploration into transcriptomic signatures for AhR safety assessment, incorporation of physiologically-relevant in vitro model systems, and investigation into chronic activation of the AhR by structurally diverse ligands will help address gaps in our understanding regarding AhR-dependent toxicities. Here, we review the role of the AhR within the GI tract, novel therapeutic modality approaches to target the AhR, key AhR-dependent safety liabilities, and relevant strategies that can be implemented to address drug safety concerns. Together, this review discusses the emerging therapeutic landscape of modalities targeting the AhR for inflammatory GI indications and offers a safety roadmap for AhR drug development.
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spelling pubmed-91398552022-05-28 Current Therapeutic Landscape and Safety Roadmap for Targeting the Aryl Hydrocarbon Receptor in Inflammatory Gastrointestinal Indications Faber, Samantha C. Lahoti, Tejas S. Taylor, Ewan R. Lewis, Lauren Sapiro, Jessica M. Toledo Sales, Vicencia Dragan, Yvonne P. Jeffy, Brandon D. Cells Review Target modulation of the AhR for inflammatory gastrointestinal (GI) conditions holds great promise but also the potential for safety liabilities both within and beyond the GI tract. The ubiquitous expression of the AhR across mammalian tissues coupled with its role in diverse signaling pathways makes development of a “clean” AhR therapeutically challenging. Ligand promiscuity and diversity in context-specific AhR activation further complicates targeting the AhR for drug development due to limitations surrounding clinical translatability. Despite these concerns, several approaches to target the AhR have been explored such as small molecules, microbials, PROTACs, and oligonucleotide-based approaches. These various chemical modalities are not without safety liabilities and require unique de-risking strategies to parse out toxicities. Collectively, these programs can benefit from in silico and in vitro methodologies that investigate specific AhR pathway activation and have the potential to implement thresholding parameters to categorize AhR ligands as “high” or “low” risk for sustained AhR activation. Exploration into transcriptomic signatures for AhR safety assessment, incorporation of physiologically-relevant in vitro model systems, and investigation into chronic activation of the AhR by structurally diverse ligands will help address gaps in our understanding regarding AhR-dependent toxicities. Here, we review the role of the AhR within the GI tract, novel therapeutic modality approaches to target the AhR, key AhR-dependent safety liabilities, and relevant strategies that can be implemented to address drug safety concerns. Together, this review discusses the emerging therapeutic landscape of modalities targeting the AhR for inflammatory GI indications and offers a safety roadmap for AhR drug development. MDPI 2022-05-21 /pmc/articles/PMC9139855/ /pubmed/35626744 http://dx.doi.org/10.3390/cells11101708 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Faber, Samantha C.
Lahoti, Tejas S.
Taylor, Ewan R.
Lewis, Lauren
Sapiro, Jessica M.
Toledo Sales, Vicencia
Dragan, Yvonne P.
Jeffy, Brandon D.
Current Therapeutic Landscape and Safety Roadmap for Targeting the Aryl Hydrocarbon Receptor in Inflammatory Gastrointestinal Indications
title Current Therapeutic Landscape and Safety Roadmap for Targeting the Aryl Hydrocarbon Receptor in Inflammatory Gastrointestinal Indications
title_full Current Therapeutic Landscape and Safety Roadmap for Targeting the Aryl Hydrocarbon Receptor in Inflammatory Gastrointestinal Indications
title_fullStr Current Therapeutic Landscape and Safety Roadmap for Targeting the Aryl Hydrocarbon Receptor in Inflammatory Gastrointestinal Indications
title_full_unstemmed Current Therapeutic Landscape and Safety Roadmap for Targeting the Aryl Hydrocarbon Receptor in Inflammatory Gastrointestinal Indications
title_short Current Therapeutic Landscape and Safety Roadmap for Targeting the Aryl Hydrocarbon Receptor in Inflammatory Gastrointestinal Indications
title_sort current therapeutic landscape and safety roadmap for targeting the aryl hydrocarbon receptor in inflammatory gastrointestinal indications
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9139855/
https://www.ncbi.nlm.nih.gov/pubmed/35626744
http://dx.doi.org/10.3390/cells11101708
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