Katrin Koellisch, Christine Blattner, Stefano Motta, Janine Wesslowski, Melanie Rothley, Simone Büchel, Savannah Sirounian, Ilenia Segatto, H. Weber, Julia Müller, Marina Grimaldi, Jutta Stober, Zoe Wammetsberger, Mengwu Pan, René Houtman, Christoph W. Grathwol, Lo-Wei Lin, Laki Buluwela, Siva K. Kolluri, Dominik Mytzka, Simak Ali, Nicole Jung, Patrick Balaguer, Sonja Thaler, Barbara Belletti, Laura Bonati, William Bourguet, Stefan Bräse, Gary Davidson, Andrew C.B. Cato
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.