Issue 10, 2024

Discovery and optimisation of pyrazolo[1,5-a]pyrimidines as aryl hydrocarbon receptor antagonists

Abstract

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.

Graphical abstract: Discovery and optimisation of pyrazolo[1,5-a]pyrimidines as aryl hydrocarbon receptor antagonists

Supplementary files

Article information

Article type
Research Article
Submitted
17 Apr 2024
Accepted
14 Jul 2024
First published
28 Aug 2024

RSC Med. Chem., 2024,15, 3477-3484

Discovery and optimisation of pyrazolo[1,5-a]pyrimidines as aryl hydrocarbon receptor antagonists

R. Bobrovs, S. Terentjeva, N. E. Olafsen, Z. Dambrauskas, A. Gulbinas, T. Maimets, I. Teino, A. Jirgensons, J. Matthews and K. Jaudzems, RSC Med. Chem., 2024, 15, 3477 DOI: 10.1039/D4MD00266K

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