(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.

The (S,R,S)-AHPC-(C3-PEG)2-C6-Cl is a versatile E3 Ligase Ligand-Linker Conjugate designed for use in PROTACs, facilitating targeted protein degradation. It combines a potent E3 ligase ligand with a flexible linker to enhance the efficiency of protein degradation. The following provides a detailed description of this molecule.

Linker: The linker in this molecule is a C3-PEG2-C6 chain, which provides moderate flexibility and optimal length for bridging the ligand and target protein. Its polyethylene glycol (PEG) segments impart hydrophilicity, improving solubility and cellular permeability, while its non-cleavable nature ensures stability during cellular processes.

Ligand: The ligand component is based on (S,R,S)-AHPC, a well-characterized E3 ligase recruiter. It features a chiral configuration that enhances binding affinity and specificity for the E3 ubiquitin ligase, thus promoting efficient ubiquitination and subsequent proteasomal degradation of the target protein.

Reactive Site: The reactive site of this conjugate is the terminal chlorine atom, which is primed for nucleophilic substitution reactions. This site is ideal for coupling with nucleophile-containing target protein ligands through reactions such as nucleophilic aromatic substitution, enabling the formation of stable covalent bonds.

Recommended Target Protein Ligand: The recommended warhead for this molecule is a nucleophile-rich moiety, such as a thiol or amine group, which can effectively engage with the chlorine reactive site. This compatibility allows for the selective and efficient degradation of target proteins, making it suitable for studies involving the validation of novel protein targets in drug discovery and development.