(S,R,S)-AHPC-PEG2-NH2 dihydrochloride

Background Introduction

(S,R,S)-AHPC-PEG2-NH2 dihydrochloride is a specialized bifunctional molecule widely utilized in the development of Proteolysis Targeting Chimeras (PROTACs). This compound features an (S,R,S)-AHPC-based E3 ligase ligand, which offers high affinity and selectivity for the von Hippel-Lindau (VHL) E3 ubiquitin ligase. The incorporation of the PEG2 linker enhances solubility and cell permeability, while the terminal amine (NH2) provides a functional handle for conjugation to target protein ligands. The strategic molecular design of (S,R,S)-AHPC-PEG2-NH2 dihydrochloride makes it a crucial building block in next-generation targeted protein degradation research and drug discovery.

Mechanism

(S,R,S)-AHPC-PEG2-NH2 dihydrochloride acts as a modular scaffold in PROTAC synthesis. Its (S,R,S)-AHPC moiety binds specifically to the VHL E3 ubiquitin ligase complex. The PEG2 linker provides optimal spatial flexibility, minimizing steric hindrance and improving the bioavailability of the resulting PROTAC molecules. The free amine group at the end of the linker allows for straightforward conjugation via amide coupling or other chemical strategies to a warhead ligand that targets the protein of interest. Once the bifunctional PROTAC brings the E3 ligase and the target protein into proximity, the ubiquitin-proteasome system is recruited, tagging the target protein for proteasomal degradation. This mechanism enables the selective and irreversible removal of disease-relevant proteins within cells.

Applications

(S,R,S)-AHPC-PEG2-NH2 dihydrochloride is extensively applied in the design and synthesis of PROTAC molecules aimed at therapeutic target validation, drug discovery, and chemical biology research. Researchers utilize this conjugate to develop customized protein degraders for cancer, neurodegenerative diseases, and other conditions involving pathogenic proteins. The product is especially valuable in creating VHL-based degraders and serves as a critical reagent for medicinal chemistry and structure-activity relationship (SAR) studies. Its applicability also extends to the development of molecular probes for investigating protein function and cellular mechanisms, enabling breakthroughs in next-generation therapeutics and targeted protein modulation.

• Polyethylene glycol (PEG2) linker improves aqueous solubility and pharmacokinetic properties for efficient PROTAC development.
• Amine-terminated design enables facile conjugation with target ligands, streamlining VHL-based PROTAC synthesis.