(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.

The (S,R,S)-AHPC-PEG6-C4-Cl E3 Ligase Ligand-Linker Conjugate plays a pivotal role in the development of PROTACs by facilitating targeted protein degradation. Its unique structural characteristics enhance the selectivity and efficacy of PROTACs, making it ideal for research applications in protein biology and drug discovery. The following provides a detailed description of this molecule.

Linker: The linker in this molecule is a PEG6, which is a polyethylene glycol chain consisting of six ethylene glycol units. This provides moderate flexibility and optimal length for bridging the ligand and target protein, while its non-cleavable nature ensures stability in diverse biological environments.

Ligand: The ligand in this conjugate is (S,R,S)-AHPC, a stereochemically defined small molecule that binds effectively to the E3 ligase. Its structural characteristics ensure high affinity and specificity, enhancing the degradation efficiency of the target protein.

Reactive Site: The reactive site is a chloroalkane moiety, designed to couple with the target protein ligand. Recommended reaction types include nucleophilic substitution reactions, which facilitate covalent attachment to the protein warhead, ensuring robust conjugation.

Recommended Target Protein Ligand: The compatible warhead for this conjugate is an electrophilic moiety such as a haloacetamide, which can form a stable covalent bond with the reactive site. This enhances the selectivity and potency of the PROTAC, making it suitable for targeting proteins with nucleophilic residues, thereby broadening the scope of experimental studies in protein degradation.