T(AHR)getting the AHR: mapping the road of a xenobiotic sensor, from disease to a therapeutic target

• Autor(a) principal: Castro-Almeida, I.
• Data de Publicação: 2023
• Outros Autores: Janowska, A., Saitch, R., Lian, Y., Delgado, A., Protze , J., Moura-Alves, P.
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: https://doi.org/10.48797/sl.2023.86
• topic: Poster

Background: The aryl hydrocarbon receptor (AHR) is a highly conserved ligand-dependent transcription factor, which recently gained recognition, beyond its role as a toxicity sensor, as a major player in different biological circumstances [1]. Our group and others have shown that AHR modulation in different scenarios, including by therapeutic drugs, impacts disease outcomes and treatment efficacy, in conditions such as cancer and bacterial infections [1-3]. For example, therapeutic drugs designed to target other molecules also bind to and modulate AHR activity [1,2]. Albeit, the extent of clinically approved drugs with AHR modulatory properties and the elicited AHR functions is largely unknown. Objective: Identify drugs with AHR modulatory properties. Methods: The AHR modulatory properties of 3178 drugs were examined using a luciferase cell reporter assay, in silico binding studies, and data analysis, through Ingenuity Pathway Analysis and data mining [2,4,5]. Results: We unbiasedly identified 228 hits as potential AHR agonists or antagonists (including known AHR ligands, validating our approach) and calculated the respective EC50s or IC50s. Next, AHR modelling studies predicted 53 agonists and 31 antagonists to bind to AHR. According to the data analysis, we classified the hits according to their roles in different pathways, diseases, and targets. We decided to initially focus on drugs with known roles in cancer or infection. An anticancer and anti-infection molecule is currently being tested for its AHR modulatory properties, and for the assessment of the AHR role(s) in its therapeutic mechanism and drug-resistance phenotypes. Further validation studies will involve in vitro and in vivo approaches (e.g. in zebrafish). Conclusions: In all, we aim to gain a deeper understanding of the biology of AHR in disease and its role in resistance mechanisms and identify potential repurposing drugs to target this receptor, paving the ground for future therapeutic approaches.