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. und Wehr, Michael C. (2024): Profiling of ERBB receptors and downstream pathways reveals selectivity and hidden properties of ERBB4 antagonists. In: iScience, Bd. 27, Nr. 2, 108839

Abstract

ERBB receptor tyrosine kinases are involved in development and diseases like cancer, cardiovascular, neu rodevelopmental, and mental disorders. Although existing drugs target ERBB receptors, the next gener ation 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 estab lished 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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin ; Medizin > Klinikum der LMU München > Klinik und Poliklink für Psychiatrie und Psychotherapie
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 25890042
• Sprache: Englisch