ArticlePloS one2014
Benzimidazoisoquinolines: a new class of rapidly metabolized aryl hydrocarbon receptor (AhR) ligands that induce AhR-dependent Tregs and prevent murine graft-versus-host disease.
Article in PloS one, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
27 citing papers in PubMed, 58 citations in OpenAlex.
- Aryl hydrocarbon receptor pharmacology-mechanisms, ligands, and therapeutic potential.Pharmacological reviews · 2026Review
- Suppression of global protein synthesis and hepatocellular carcinoma cell growth by Benzimidazoisoquinoline, 4,11-Dichloro-BBQ.Biochemical pharmacology · 2025Article
- Activation of the aryl hydrocarbon receptor improves allergen-specific immunotherapy of murine allergic airway inflammation: a novel adjuvant option?Frontiers in immunology · 2024Article
- Suppression of Ah Receptor (AhR) increases the aggressiveness of TNBC cells and 11-Cl-BBQ-activated AhR inhibits their growth.Biochemical pharmacology · 2023Article
- Induction of Aryl Hydrocarbon Receptor-Mediated Cancer Cell-Selective Apoptosis in Triple-Negative Breast Cancer Cells by a High-Affinity Benzimidazoisoquinoline.ACS pharmacology & translational science · 2023Article
- 11-Cl-BBQ, a select modulator of AhR-regulated transcription, suppresses lung cancer cell growth via activation of p53 and p27The FEBS journal · 2023Article
- Tumor-Suppressive Functions of the Aryl Hydrocarbon Receptor (AhR) and AhR as a Therapeutic Target in Cancer.Biology · 2023Review
- Activation of the aryl hydrocarbon receptor inhibits neuropilin-1 upregulation on IL-2-responding CD4Frontiers in immunology · 2023Article
- Dissecting the regulatory network of transcription factors in T cell phenotype/functioning during GVHD and GVT.Frontiers in immunology · 2023Review
- Lactobacillus reuteri tryptophan metabolism promotes host susceptibility to CNS autoimmunity.Microbiome · 2022Article
- Consensus on the Key Characteristics of Immunotoxic Agents as a Basis for Hazard Identification.Environmental health perspectives · 2022Article
- Targeting AhR as a Novel Therapeutic Modality against Inflammatory Diseases.International journal of molecular sciences · 2021Review
- Discovery and Mechanistic Characterization of a Select Modulator of AhR-regulated Transcription (SMAhRT) with Anti-cancer Effects.Apoptosis : an international journal on programmed cell death · 2021Article
- Tryptophan Metabolism, Regulatory T Cells, and Inflammatory Bowel Disease: A Mini Review.Mediators of inflammation · 2020Review
- Dietary Indole-3-Carbinol Activates AhR in the Gut, Alters Th17-Microbe Interactions, and Exacerbates Insulitis in NOD Mice.Frontiers in immunology · 2020Article
- TCDD, FICZ, and Other High Affinity AhR Ligands Dose-Dependently Determine the Fate of CD4+ T Cell Differentiation.Toxicological sciences : an official journal of the Society of Toxicology · 2018Article
- AhR activation increases IL-2 production by alloreactive CD4European journal of immunology · 2017Article
- Article
- Role of the aryl hydrocarbon receptor in carcinogenesis and potential as an anti-cancer drug target.Archives of toxicology · 2017Review
- The aryl hydrocarbon receptor is required for induction of p21cip1/waf1 expression and growth inhibition by SU5416 in hepatoma cells.Oncotarget · 2017Article
Corrections and comments
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Authors and funding
10 authors at 1 institution in 1 country.
Funding
Abstract
The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that plays multiple roles in regulation of immune and inflammatory responses. The ability of certain AhR ligands to induce regulatory T cells (Tregs) has generated interest in developing AhR ligands for therapeutic treatment of immune-mediated diseases. To this end, we designed a screen for novel Treg-inducing compounds based on our understanding of the mechanisms of Treg induction by the well-characterized immunosuppressive AhR ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). We screened a ChemBridge small molecule library and identified 10-chloro-7H-benzimidazo[2,1-a]benzo[de]Iso-quinolin-7-one (10-Cl-BBQ) as a potent AhR ligand that was rapidly metabolized and not cytotoxic to proliferating T cells. Like TCDD,10-Cl-BBQ altered donor CD4(+) T cell differentiation during the early stages of a graft versus host (GVH) response resulting in expression of high levels of CD25, CTLA-4 and ICOS, as well as several genes associated with Treg function. The Treg phenotype required AhR expression in the donor CD4(+) T cells. Foxp3 was not expressed in the AhR-induced Tregs implicating AhR as an independent transcription factor for Treg induction. Structure-activity studies showed that unsubstituted BBQ as well as 4, 11-dichloro-BBQ were capable of inducing AhR-Tregs. Other substitutions reduced activation of AhR. Daily treatment with 10-Cl-BBQ during the GVH response prevented development of GVH disease in an AhR-dependent manner with no overt toxicity. Together, our data provide strong support for development of select BBQs that activate the AhR to induce Tregs for treatment of immune-mediated diseases.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.