(S,R,S)-AHPC-PEG2-C4-Cl

Background Introduction

(S,R,S)-AHPC-PEG2-C4-Cl is a high-purity E3 ligase ligand-linker conjugate specifically engineered for targeted protein degradation applications. This compound is based on the AHPC (aryl hydrocarbon receptor protein complex) moiety, renowned for its ability to recruit the Von Hippel-Lindau (VHL) E3 ubiquitin ligase within the cell. By integrating a PEG2-C4 linker and a terminal chloride group, (S,R,S)-AHPC-PEG2-C4-Cl offers a versatile building block for the synthesis of PROTAC (Proteolysis Targeting Chimera) molecules—a revolutionary approach in the development of next-generation therapeutics aimed at depleting disease-causing proteins.

Mechanism

The mechanism of (S,R,S)-AHPC-PEG2-C4-Cl centers around targeted protein degradation. The AHPC core binds selectively to the VHL E3 ubiquitin ligase, while the PEG2-C4 linker serves as a flexible and hydrophilic spacer, improving solubility and spatial orientation. The terminal chloride functionality allows for efficient coupling to diverse protein-targeting warheads. When incorporated into a PROTAC, this ligand-linker conjugate facilitates the simultaneous recruitment of the target protein and the E3 ligase, enabling ubiquitination of the target protein and subsequent degradation via the proteasome pathway.

Applications

(S,R,S)-AHPC-PEG2-C4-Cl is an essential intermediate for researchers developing novel PROTAC molecules. Its applications span chemical biology, drug discovery, and functional genomics. Specifically, it is ideal for constructing bifunctional PROTACs that selectively degrade disease-relevant targets, validate druggable proteins, and explore new therapeutic pathways. The product’s optimized linker length and reactivity enhance cell permeability and pharmacokinetic profiles, making it a preferred tool for studying targeted protein degradation in both in vitro and in vivo research models.

• Chloro-functionalized terminus supports efficient conjugation to diverse protein ligands for versatile PROTAC design.
• Incorporates a PEG2-based flexible linker, optimizing solubility and cell permeability for improved PROTAC performance.

The E3 Ligase Ligand-Linker Conjugate (S,R,S)-AHPC-PEG2-C4-Cl plays a pivotal role in the development of PROTACs by facilitating targeted protein degradation. This conjugate combines a specific E3 ligase ligand with a linker and reactive site, optimizing the degradation of target proteins. The following provides a detailed description of this molecule.

Linker: The linker in (S,R,S)-AHPC-PEG2-C4-Cl is a PEG2-C4 chain, offering moderate length and flexibility. Its polyethylene glycol (PEG) component enhances solubility and permeability, while the C4 segment provides structural support. This linker is non-cleavable, ensuring stability during the degradation process.

Ligand: The ligand in this molecule is AHPC, a derivative known for its high affinity and specificity towards the E3 ligase. Its stereochemistry contributes to the efficient recruitment of the ligase, promoting the ubiquitination of the target protein.

Reactive Site: The reactive site of this conjugate is a chloride moiety, which facilitates coupling with the target protein ligand. Suitable reaction types include nucleophilic substitution, allowing for a robust and selective attachment to the target.

Recommended Target Protein Ligand: The recommended warhead for this molecule is a nucleophilic amine or thiol group, which complements the chloride reactive site. This compatibility ensures efficient binding and degradation of the target protein. Such a warhead is advantageous in applications requiring precise modulation of protein levels, making it valuable for research into cellular processes and protein function.