(S,R,S)-AHPC-PEG6-C4-Cl

Background Introduction

(S,R,S)-AHPC-PEG6-C4-Cl is a specialized E3 ligase ligand-linker conjugate designed for targeted protein degradation. As a key component in the development of PROTAC (Proteolysis Targeting Chimera) molecules, it harnesses the specificity of E3 ligase binding to facilitate selective protein knockdown. The compound incorporates a high-affinity VH032-based VHL ligand (AHPC), optimized with a PEG6 linker for improved solubility and cellular permeability, and a functional C4-chloro handle for coupling to target-binding ligands.

Mechanism

(S,R,S)-AHPC-PEG6-C4-Cl operates as a modular E3 ligase ligand-linker, serving as one half of bifunctional PROTAC compounds. The AHPC moiety selectively recruits the von Hippel-Lindau (VHL) E3 ubiquitin ligase, while the PEG6 spacer affords flexibility and hydrophilicity. The terminal C4-chloro group enables conjugation with various target protein ligands. Once assembled into a complete PROTAC, the molecule brings the E3 ligase into proximity with the protein of interest, leading to its ubiquitination and subsequent proteasomal degradation.

Applications

(S,R,S)-AHPC-PEG6-C4-Cl is widely used in the creation and optimization of PROTACs aimed at targeted protein degradation for chemical biology research and drug discovery. Its versatile linker system supports conjugation to diverse small-molecule ligands, making it ideal for developing novel degraders against oncogenic proteins, epigenetic regulators, or other disease-relevant targets. Furthermore, it serves as a key reagent in structure-activity relationship (SAR) studies and mechanism-of-action assays in preclinical research.