Distinct 2-phenylimidazo[1,2-a]pyridine derivatives that inhibit breast cancer cell proliferation identified as aryl hydrocarbon receptor ligands

X15695 is a 2-phenylimidazo[1,2-a] pyridine derivative previously described as an orally active, selective estrogen receptor (ER) degrader that inhibits the proliferation of ER⁺ breast cancer cells. Here, we show that X15695 and derivatives are aryl hydrocarbon receptor (AHR) ligands. Knockout of AHR abolishes the anti-proliferative property of the imidazopyridine derivatives. In the presence of estradiol, X15695 and derivatives outperform the standard of care drug fulvestrant in suppressing the growth of ER⁺ breast cancer cells, expressing either the wild-type or clinically relevant ER mutant forms (Y537S and D538G) and of patient-derived organoids established from ER⁺ tumors. Using computational techniques, we discovered that a low pKa value resulting from electron-withdrawing substituents in the 2-phenylimidazo[1,2-a] pyridine compounds is a key feature that identifies them as potent AHR ligands, leading to the potential discovery of additional derivatives for future therapeutic development.