(S,R,S)-AHPC-PEG3-Alkyne

Background Introduction

(S,R,S)-AHPC-PEG3-Alkyne is a versatile E3 ligase ligand-linker conjugate designed for targeted protein degradation research. This molecule integrates a high-affinity von Hippel-Lindau (VHL) E3 ligase ligand (AHPC), a triethylene glycol (PEG3) spacer for optimal flexibility and solubility, and a terminal alkyne group suitable for click chemistry. As the demand for novel tools in the field of targeted protein degradation and PROTAC (Proteolysis Targeting Chimera) technology grows, (S,R,S)-AHPC-PEG3-Alkyne enables researchers to develop innovative bifunctional degraders and study diverse protein targets.

Mechanism

The mechanism of action of (S,R,S)-AHPC-PEG3-Alkyne centers on its role as a modular building block for PROTAC synthesis. The compound covalently binds to VHL, an E3 ubiquitin ligase component, via the AHPC ligand. The PEG3 linker provides the necessary spatial separation and flexibility for efficient ternary complex formation. Meanwhile, the alkyne terminus allows for facile conjugation to target-binding warheads using copper-catalyzed azide-alkyne cycloaddition (CuAAC, or 'click chemistry'). When incorporated into a PROTAC construct, (S,R,S)-AHPC-PEG3-Alkyne brings the E3 ligase in close proximity to the protein of interest, promoting its ubiquitination and subsequent degradation by the proteasome.

Applications

(S,R,S)-AHPC-PEG3-Alkyne is widely utilized in the rational design and synthesis of PROTAC molecules aimed at targeted protein degradation. Its alkyne group facilitates modular 'click' ligation to various azide-tagged ligands, supporting the rapid development of a diversified PROTAC library. Applications include exploration of new protein targets, elucidation of the ubiquitin-proteasome pathway, and preclinical drug discovery research. This conjugate is also valuable for generating tool compounds to probe protein function in cellular systems, and for structure-activity relationship (SAR) studies in the optimization of next-generation degraders.