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Updated: Jul 17, 2025

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Targeting Cytotoxic Agents through EGFR-Mediated Covalent Binding and Release

Pasquale A Morese1, Nahoum Anthony2, Michael Bodnarchuk3

  • 1Cancer Research Horizons Therapeutic Innovation, Newcastle University Centre for Cancer, Chemistry, School of Natural and Environmental Sciences, Newcastle University, Bedson Building, Newcastle upon Tyne NE1 7RU, U.K.

Journal of Medicinal Chemistry
|August 30, 2023
PubMed

Insights

Researchers developed a new method for targeted cancer therapy by attaching cytotoxic drugs to covalent inhibitors. This approach ensures drug release specifically at tumor sites, improving treatment selectivity and reducing side effects.

Area of Science:

  • Medicinal Chemistry
  • Drug Delivery
  • Oncology

Background:

  • Cytotoxic chemotherapy lacks selectivity, harming healthy cells.
  • Targeted drug delivery to tumors is a critical goal in cancer research.
  • Covalent inhibitors offer a potential platform for targeted drug delivery.

Purpose of the Study:

  • To adapt covalent inhibitors for targeted delivery of cytotoxic agents.
  • To investigate the release mechanism of conjugated drugs via Michael acceptor addition-elimination.
  • To develop novel targeted therapeutics based on this delivery strategy.

Main Methods:

  • Synthesis of covalent epidermal growth factor receptor (EGFR) inhibitors as 5-fluorouracil (5FU) derivatives.
  • Utilizing Michael acceptors for drug conjugation.
  • Employing mass spectrometry and NMR to study drug binding and release.

Main Results:

  • Demonstrated release of conjugated 5FU upon thiol addition in model systems.
  • Showed that 5FU release is dependent on compound electronics and geometry.
  • Confirmed EGFR binding and 5FU release from an anilinoquinazoline acrylate ester conjugate.

Conclusions:

  • Acrylates can facilitate the release of conjugated molecules upon covalent protein binding.
  • This mechanism holds promise for developing targeted cancer therapeutics.
  • The study establishes a new strategy for selective cytotoxic drug delivery.

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