(S,R,S)-AHPC-PEG1-NH2

Background Introduction

(S,R,S)-AHPC-PEG1-NH2 is a cutting-edge E3 ligase ligand-linker conjugate widely utilized in the design and synthesis of Proteolysis Targeting Chimeras (PROTACs). This unique bifunctional molecule is based on the AHPC scaffold, a high-affinity ligand for the von Hippel-Lindau (VHL) E3 ubiquitin ligase, and incorporates a short PEG1 linker ending with an amine group for flexible conjugation with target-binding moieties.

Mechanism

The mechanism of (S,R,S)-AHPC-PEG1-NH2 centers on its ability to recruit the VHL E3 ubiquitin ligase complex. When (S,R,S)-AHPC-PEG1-NH2 is coupled to a ligand for a target protein, the resulting PROTAC molecule brings the target protein into close proximity with VHL. This proximity enables the transfer of ubiquitin molecules from the E2 conjugating enzyme to the target protein, marking it for recognition and subsequent degradation by the proteasome. The PEG1 spacer enhances solubility and provides spatial flexibility, optimizing ternary complex formation.

Applications

(S,R,S)-AHPC-PEG1-NH2 is extensively employed as a versatile intermediate in PROTAC development. Its primary application is in the synthesis of new PROTACs designed for selective degradation of disease-relevant proteins, enabling both target validation in drug discovery and therapeutics innovation. Researchers utilize this conjugate for structure-activity relationship (SAR) studies, improving proteome editing capabilities, and exploring degraders for kinases, epigenetic regulators, and other difficult-to-drug targets. Its PEG-linked amine functionality allows seamless coupling to a wide variety of target ligands, making it a vital tool in next-generation protein degradation research.

• PEG1 linker offers increased solubility and improved pharmacokinetic properties for PROTAC molecules.
• Amine terminal group ensures versatile conjugation with target ligands or payloads for efficient VHL E3 ligase recruitment.