Modular Vinyl Phosphonamidates for Cysteine-Directed Protein Targeting

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.