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Cited by 16Inflammatory Bowel DiseaseToxic Organic Pollutants ImpactPharmacogenetics and Drug Metabolism

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

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Faber, Samantha, Lahoti, Tejas, Taylor, Ewan, Lewis, Lauren, Sapiro, Jessica, Toledo Sales, Vicencia, Dragan, Yvonne, Jeffy, Brandon·2022·Cells
DOI 10.3390/cells11101708PMC PMC9139855
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Abstract

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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Cited by

Sorted by citations

Authors
Faber, S., Lahoti, T., Taylor, E., Lewis, L., Sapiro, J., Toledo Sales, V., Dragan, Y., & Jeffy, B.
Affiliations
  • Takeda (United States) (US)
  • Investigative Toxicology, Drug Safety Research & Evaluation, Takeda Development Center Americas, Inc., Cambridge, MA 02139, USA
Corresponding author
Faber, Samantha
ORCID
Venue
Cells
Publisher
MDPI AG
Published
2022-05-21
Volume
11
Issue
10
Pages
1708
ISSN
2073-4409 (ISSN-L)
DOI
10.3390/cells11101708
PMC
PMC9139855
OpenAlex
W4281257096
Cited by
16
References
16
Citations by year
2026: 5 · 2025: 4 · 2024: 5 · 2023: 1 · 2022: 1
FWCI
0.42
Type
journal article
Language
en
Open access
Licence
Locations
  • Cells (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
Takeda Development Center Americas, Inc.
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Inflammatory Bowel Disease
  • Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Toxic Organic Pollutants Impact
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
Keywords
aryl hydrocarbon receptor, drug safety, PROTACs, oligonucleotide therapeutics, microbial therapeutics, in vitro toxicity models, drug development
MeSH terms
Animals, Ligands, Mammals, Signal Transduction, Receptors, Aryl Hydrocarbon, Gastrointestinal Tract

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