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Synergistic SuFEx-Driven Covalent Cancer Therapy Using a HER2/EGFR Bivalent Affinity Protein Drug.

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This study engineered a bivalent protein drug using sulfur fluoride exchange (SuFEx) chemistry for enhanced covalent crosslinking. The novel drug demonstrated superior tumor targeting and inhibition in pancreatic cancer models.

Keywords:
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Area of Science:

  • Biochemistry
  • Chemical Biology
  • Drug Discovery

Background:

  • Sulfur fluoride exchange (SuFEx) chemistry integration into proteins advances biological applications.
  • Suboptimal reaction rates of SuFEx in proteins hinder effective covalent crosslinking.

Purpose of the Study:

  • To develop a bivalent affinity protein drug using maleimide-substituted aryl fluorosulfate (MFS) linkers for dual targeting of HER2 and EGFR.
  • To enhance covalent crosslinking performance and therapeutic efficacy through multivalent interactions.

Main Methods:

  • Chemical coupling of MFS linkers to a dual-targeting affinity protein drug.
  • Evaluation of covalent cross-link performance, intracellular uptake, and tumor retention.
  • Assessment of antitumor efficacy in HER2/EGFR-positive pancreatic tumor models.

Main Results:

  • The bivalent drug showed significantly enhanced covalent cross-link performance (440%-630% higher than monovalent).
  • Achieved >80% covalent binding efficiency within 12 hours, with increased intracellular uptake and tumor retention.
  • Demonstrated extraordinary antitumor efficacy with a 90.4% tumor inhibition rate in pancreatic cancer models.

Conclusions:

  • SuFEx-engineered bivalent targeted strategy enhances covalent protein drug design.
  • The developed bivalent affinity protein drug offers a promising platform for advanced cancer therapeutics.
  • This approach significantly improves drug delivery and efficacy for HER2/EGFR-positive tumors.