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

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Lukša Popović1,2, Jan P Wintgens1,2, Yuxin Wu1

  • 1Research Group Cell Signalling, Department of Psychiatry and Psychotherapy, LMU University Hospital, LMU Munich, Nussbaumstrasse 7, 80336 Munich, Germany.

Iscience
|February 2, 2024
PubMed

Insights

A new assay, ERBBprofiler, monitors all ERBB receptor activity and pathways in cells. This tool aids in developing more selective drugs for cancer and other diseases by distinguishing therapeutic effects from side effects.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Epidermal Growth Factor Receptor (EGFR) family (ERBB) kinases are crucial in cellular processes and implicated in various diseases, including cancers and developmental disorders.
  • Current ERBB-targeting drugs lack sufficient selectivity, leading to off-target effects and necessitating improved therapeutic strategies.
  • Understanding ERBB signaling pathways is vital for developing next-generation therapeutics with enhanced efficacy and reduced toxicity.

Purpose of the Study:

  • To develop and validate a novel, high-throughput assay, ERBBprofiler, for simultaneous monitoring of all ERBB receptor activity and associated physiological pathways in living cells.
  • To utilize ERBBprofiler to differentiate on-target drug effects from off-target and off-pathway side effects of ERBB antagonists.
  • To assess the utility of ERBBprofiler in characterizing known ERBB antagonists and identifying novel drug properties, thereby guiding early-stage drug development.

Main Methods:

  • Development of a multilevel barcoded reporter profiling assay (ERBBprofiler) enabling simultaneous measurement of ERBB targets and key signaling pathways.
  • Application of ERBBprofiler to profile eight established ERBB antagonists, including pyrotinib.
  • Inclusion of two novel ERBB4-selective lead compounds in the profiling to assess their therapeutic potential.

Main Results:

  • ERBBprofiler successfully confirmed known activities of established ERBB antagonists.
  • The assay revealed previously uncharacterized properties of ERBB antagonists, such as pyrotinib's specific preference for ERBB4 over EGFR.
  • Profiling of two lead compounds demonstrated their selective targeting of ERBB4, indicating potential for clinical development.

Conclusions:

  • The developed ERBBprofiler assay provides a powerful tool for multiparametric profiling of ERBB-targeted drugs in a cellular context.
  • This approach facilitates the distinction between desired therapeutic outcomes and unintended side effects, crucial for drug optimization.
  • ERBBprofiler can significantly guide early-stage drug discovery and development, paving the way for more effective and safer therapeutics for ERBB-related diseases.
Keywords:
BiochemistryBiological sciencesCell biologyNatural sciencesPharmacology

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