(S,R,S)-AHPC-(C3-​PEG)​2-​C6-​Cl

Background Introduction

(S,R,S)-AHPC-(C3-PEG)2-C6-Cl is a specialized E3 ligase ligand-linker conjugate designed for targeted protein degradation using the PROTAC (Proteolysis Targeting Chimera) technology. This compound integrates the high-affinity AHPC ligand for the VHL (von Hippel-Lindau) E3 ubiquitin ligase, a bifunctional PEG-based linker for increased flexibility and solubility, and a reactive terminal chlorinated alkyl handle allowing for further conjugation with diverse warheads targeting proteins of interest.

Mechanism

The mechanism of (S,R,S)-AHPC-(C3-PEG)2-C6-Cl is rooted in the principles of PROTAC-mediated targeted protein degradation. The AHPC moiety selectively binds to the VHL E3 ligase, recruiting the cellular ubiquitination machinery. The PEG linker imparts optimal spatial orientation and solubility, reducing steric hindrance and increasing cell permeability. The terminal chloroalkyl group offers a conjugation handle for attaching ligands of target proteins (POIs). When conjugated to a target binder, the resultant bifunctional PROTAC molecule induces proximity between the POI and the E3 ligase, promoting ubiquitination and subsequent proteasomal degradation of the target protein.

Applications

(S,R,S)-AHPC-(C3-PEG)2-C6-Cl is widely employed as a modular scaffold in the development of PROTAC molecules, enabling rapid assembly of customized degraders for novel therapeutic targets. It is ideal for medicinal chemistry, chemical biology, target validation, and drug discovery programs aiming to evaluate new protein targets via induced degradation. Its versatile linker design and reactive terminal group facilitate efficient synthesis of PROTACs and related protein-degrading conjugates, making it a valuable tool for research in oncology, neurodegenerative diseases, and other fields where targeted protein knockdown is desired.