Distinct 2-phenylimidazo[1,2- a]pyridine derivatives that inhibit breast cancer cell proliferation identified as AHR ligands PMID: 42181287

ADC Targets in Oncology

2026-04-10

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

iScience. 2026 Apr 29;29(6):115936. doi: 10.1016/j.isci.2026.115936.

Katrin Koellisch ¹ , Christine Blattner ² , Stefano Motta ³ , Janine Wesslowski ¹ , Melanie Rothley ¹ , Simone Büchel ¹ , Savannah Sirounian ⁴ , Ilenia Segatto ⁵ , Hanna T Weber ⁶ , Julia Müller ² , Marina Grimaldi ⁷ , Jutta Stober ² , Zoe Wammetsberger ¹ , Mengwu Pan ² , René Houtman ⁸ , Christoph W Grathwol ¹ , Lo-Wei Lin ⁹ , Laki Buluwela ¹⁰ , Siva Kumar Kolluri ⁹ ¹¹ , Dominik Mytzka ¹² , Simak Ali ¹⁰ , Nicole Jung ¹ , Patrick Balaguer ⁷ , Sonja Thaler ⁶ , Barbara Belletti ⁵ , Laura Bonati ³ , William Bourguet ⁴ , Stefan Bräse ¹ ¹³ , Gary Davidson ¹ , Andrew C B Cato ¹

Affiliations

1. Institute of Biological and Chemical Systems - Functional Molecular Systems, Karlsruhe Institute of Technology, Kaiserstraße 12, 76131 Karlsruhe, Germany.
2. Institute of Biological and Chemical Systems - Biological Information Processing, Karlsruhe Institute of Technology, Kaiserstraße 12, 76131 Karlsruhe, Germany.
3. Department of Earth and Environmental Sciences, University of Milano-Bicocca, Piazza della Scienza 1, 20126 Milan, Italy.
4. CBS (Centre de Biologie Structurale), University Montpellier, CNRS, Inserm, Montpellier, France.
5. Unit of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, National Cancer Institute, Aviano, Italy.
6. European Center for Angioscience, Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany.
7. IRCM (Institut de Recherche en Cancérologie de Montpellier), Inserm U1194, University Montpellier, ICM, Montpellier, France.
8. Precision Medicine Lab, Oss, the Netherlands.
9. Cancer Research Laboratory, Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR, USA.
10. Department of Surgery and Cancer, Imperial College London, London W12 0NN, UK.
11. Linus Pauling Institute, Oregon State University, Corvallis, OR, USA.
12. Institute of Pharmacy and Molecular Biotechnology IPMB, Heidelberg University, 69120 Heidelberg, Germany.
13. Institute of Organic Chemistry, Karlsruhe Institute of Technology, Kaiserstraße 12, 76131 Karlsruhe, Germany.

Abstract

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.

Keywords

cancer; cell biology.