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Modular Vinyl Phosphonamidates for Cysteine-Directed Protein Targeting.

Christian E Stieger1,2, Charlotte Völkel1,3, Mathias B Bertelsen1

  • 1Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Robert-Rössle-Straße 10, 13125 Berlin, Germany.

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|February 10, 2026
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Summary
This summary is machine-generated.

Vinyl phosphonamidates (VPAs) are novel cysteine electrophiles offering improved selectivity for covalent inhibitor development. These compounds show reduced off-target effects and enable targeted protein degradation via PROTACs.

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Area of Science:

  • Medicinal Chemistry
  • Chemical Biology
  • Drug Discovery

Background:

  • Covalent inhibitors targeting cysteine residues are vital in drug discovery and proteomics.
  • Existing electrophiles like chloroacetamides and acrylamides have limitations in selectivity.

Purpose of the Study:

  • Introduce vinyl phosphonamidates (VPAs) as a new class of selective cysteine electrophiles.
  • Evaluate VPA reactivity, selectivity, and utility in developing covalent inhibitors and PROTACs.

Main Methods:

  • Assessed VPA reactivity with glutathione and in human cell lysate.
  • Developed VPA-functionalized Afatinib and Ibrutinib derivatives.
  • Utilized gel-based and mass spectrometry-based activity-based protein profiling (ABPP).
  • Constructed a VPA-based proteolysis targeting chimera (PROTAC).

Main Results:

  • VPAs exhibit lower intrinsic reactivity than traditional electrophiles.
  • VPA derivatives showed limited nonspecific reactivity and reduced off-target engagement.
  • VPA-functionalized drugs maintained inhibitor efficiency.
  • A VPA-based PROTAC was successfully developed for targeted protein degradation.

Conclusions:

  • VPAs represent a selective and modular electrophile class for cysteine-directed covalent modification.
  • VPAs expand the chemical space for developing covalent inhibitors with favorable reactivity profiles.
  • VPAs facilitate targeted protein degradation strategies through PROTAC development.