(S,R,S)-AHPC-PEG4-Alkyne

Background Introduction

(S,R,S)-AHPC-PEG4-Alkyne is a specialized E3 ligase ligand-linker conjugate engineered for use in the development of PROTACs (Proteolysis Targeting Chimeras) and related targeted protein degradation technologies. The molecule features the high-affinity von Hippel-Lindau (VHL) ligand (AHPC) in its stereochemically defined (S,R,S) configuration, a flexible tetraethylene glycol (PEG4) linker, and an alkyne functional group for versatile conjugation with targeting warheads. Such heterobifunctional molecules are essential to enable next-generation therapeutics and research tools for selective protein knockdown.

Mechanism

(S,R,S)-AHPC-PEG4-Alkyne operates by leveraging the ubiquitin-proteasome system through PROTAC technology. The AHPC moiety specifically recruits the VHL E3 ubiquitin ligase complex, while the PEG4 linker provides spatial flexibility. The terminal alkyne group enables bioorthogonal conjugation, commonly via click chemistry, to a ligand or warhead targeting a protein of interest. When incorporated into a PROTAC molecule, this conjugate brings the E3 ligase into close proximity with the target protein, resulting in its ubiquitination and subsequent degradation by the proteasome. This mechanism allows for the targeted elimination of disease-relevant or previously 'undruggable' proteins.

Applications

(S,R,S)-AHPC-PEG4-Alkyne is widely used in medicinal chemistry and chemical biology for the design and synthesis of PROTACs targeting a variety of proteins, such as kinases, transcription factors, and epigenetic regulators. Its versatile alkyne group supports modular assembly via click chemistry, facilitating the rapid development of custom degraders. Applications include validation of new drug targets, creation of tool compounds for functional genomics, cancer research, neurodegenerative disease studies, and the broader development of targeted protein degradation therapeutics. The compound's structure also enables labeling or imaging studies when conjugated with appropriate probes.

• Alkyne-functionalized PEG4 linker enables efficient and versatile click chemistry conjugation for building diverse PROTACs.
• High specificity and affinity for the VHL E3 ligase, ensuring robust target protein ubiquitination in PROTAC applications.