Distinct 2-phenyl-imidazo[1, 2α] pyridine derivatives drive ER degradation and selectively impair proliferation of ER ⁺ breast cancer cells via the aryl hydrocarbon receptor

X15695 is a 2-phenyl-imidazo[1, 2α] pyridine derivative identified as an orally active, selective oestrogen receptor (ER) degrader that inhibits the proliferation of ER ⁺ breast cancer cells. Here, we show that X15695 is an aryl hydrocarbon receptor (AHR) ligand that stabilises the AHR more efficiently than its classical ligand, indirubin. X15695 enables AHR to form a complex with the ER, promoting its proteasomal degradation. In the presence of oestradiol, X15695 outperforms the standard of care drug fulvestrant in suppressing the growth of ER ⁺ breast cancer cells, either expressing the wild-type or clinically relevant ER mutant forms (Y537S and D538G), and of patient-derived xenograft organoids established from ER ⁺ tumours. Using computational techniques, we discovered that a low pKa value resulting from electron-withdrawing substituents in the 2-phenyl-imidazo[1, 2α] pyridine compounds is a key feature that identify them as potent AHR ligands, leading to the potential discovery of additional derivatives for future therapeutic development.