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

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 homology model-based high-throughput virtual screening and were experimentally verified in a luciferase reporter gene assay. The identified pyrazolo[1,5-]pyrimidine-based AHR antagonist 7 (IC = 650 nM) was systematically optimised to elucidate structure-activity relationships and reach low nanomolar AHR antagonistic potency (7a, IC = 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.