Profiling of ERBB receptors and downstream pathways reveals selectivity and hidden properties of ERBB4 antagonists

Popović, Lukša; Wintgens, Jan P.; Wu, Yuxin; Brankatschk, Ben; Menninger, Sascha; Degenhart, Carsten; Jensen, Niels; Wichert, Sven P.; Klebl, Bert; Rossner, Moritz J.; Wehr, Michael C. (2024): Profiling of ERBB receptors and downstream pathways reveals selectivity and hidden properties of ERBB4 antagonists. iScience, 27 (2): 108839. ISSN 25890042

Abstract

ERBB receptor tyrosine kinases are involved in development and diseases like cancer, cardiovascular, neurodevelopmental, and mental disorders. Although existing drugs target ERBB receptors, the next generation of drugs requires enhanced selectivity and understanding of physiological pathway responses to improve efficiency and reduce side effects. To address this, we developed a multilevel barcoded reporter profiling assay, termed ‘ERBBprofiler’, in living cells to monitor the activity of all ERBB targets and key physiological pathways simultaneously. This assay helps differentiate on-target therapeutic effects from off-target and off-pathway side effects of ERBB antagonists. To challenge the assay, eight established ERBB antagonists were profiled. Known effects were confirmed, and previously uncharacterized properties were discovered, such as pyrotinib’s preference for ERBB4 over EGFR. Additionally, two lead compounds selectively targeting ERBB4 were profiled, showing promise for clinical trials. Taken together, this multiparametric profiling approach can guide early-stage drug development and lead to improved future therapeutic interventions.

• Doc-Type: Article (LMU Hospital)
• Organisational unit (Faculties): 07 Medicine > Medical Center of the University of Munich > Clinic and Polyclinic for Psychiatry and Psychotherapy
• DFG subject classification of scientific disciplines: Life sciences
• DFG: Funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - 491502892