Discovery and Optimisation of Pyrazolo[1,5-a]Pyrimidines as Aryl Hydrocarbon Receptor Antagonists
RSC Medicinal Chemistry 2024
Raitis Bobrovs, Svetlana Terentjeva, Ninne Elise Olafsen, Zilvinas Dambrauskas, Antanas Gulbinas, Toivo Maimets, Indrek Teino, Aigars Jirgensons, jason Matthews, Kristaps Jaudzems

The aryl hydrocarbon receptor (AHR) is a versatile ligand-dependent transcription factor involved in diverse biological processes, from metabolic adaptations to immune system regulation. Recognising its pivotal role in cancer immunology, AHR has become a promising target for cancer therapy. Here we report the discovery and structure-activity relationship studies of novel AHR antagonists. The potential AHR antagonists were identified via homology model-based high-throughput virtual screening and were experimentally verified in a luciferase reporter gene assay. The identified pyrazolo[1,5-a]pyrimidine-based AHR antagonist 7 (IC50 = 650 nM) was systematically optimised to elucidate structure-activity relationships and reach low nanomolar AHR antagonistic potency (7a, IC50 = 31 nM). Overall, the findings presented here provide new starting points for AHR antagonist development and offer insightful information on AHR antagonist structure-activity relationships.


DOI
10.1039/d4md00266k
Hipersaite
https://pubs.rsc.org/en/content/articlelanding/2024/md/d4md00266k

Bobrovs, R., Terentjeva, S., Olafsen, N., Dambrauskas, Z., Gulbinas, A., Maimets, T., Teino, I., Jirgensons, A., Matthews, j., Jaudzems, K. Discovery and Optimisation of Pyrazolo[1,5-a]Pyrimidines as Aryl Hydrocarbon Receptor Antagonists. RSC Medicinal Chemistry, 2024, Vol. 15, No. 10, 3477.-3484.lpp. e-ISSN 2632-8682. Pieejams: doi:10.1039/d4md00266k

Publikācijas valoda
English (en)
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