(S,R,S)-AHPC-PEG5-Alkyne

Background Introduction

(S,R,S)-AHPC-PEG5-Alkyne is a specialized E3 ligase ligand-linker conjugate designed for targeted protein degradation applications. Serving as a key building block in the development of Proteolysis Targeting Chimeras (PROTACs), this molecule features an (S,R,S)-AHPC derivative that selectively recruits the von Hippel-Lindau (VHL) E3 ubiquitin ligase, connected via a PEG5 (polyethylene glycol) spacer to a terminal alkyne, enabling easy attachment to custom warheads or targets.

Mechanism

The mechanism of (S,R,S)-AHPC-PEG5-Alkyne is rooted in its dual-functional architecture. The (S,R,S)-AHPC moiety binds specifically to the VHL E3 ligase complex, while the PEG5 linker imparts flexibility and optimal distance between the recruited ligase and the target protein. The terminal alkyne group facilitates bioorthogonal conjugation, often via click chemistry, to various protein-targeting ligands. When incorporated into a PROTAC, it mediates proximity-induced ubiquitination and subsequent proteasomal degradation of the target protein, harnessing the body's natural protein disposal pathway for selective and potent knockdown.

Applications

(S,R,S)-AHPC-PEG5-Alkyne is widely used in PROTAC research and development for targeted protein degradation. Its primary applications include: custom synthesis of novel PROTAC molecules through click chemistry, structure-activity relationship (SAR) studies involving linker optimization, and validation of VHL-based degradation strategies in cell biology and chemical biology research. Researchers also utilize this conjugate for rapid prototyping of degraders against disease-relevant proteins, enabling drug discovery efforts in oncology, neurodegeneration, and other therapeutic areas. Its versatility makes it a valuable tool for advancing next-generation targeted therapies.