(S,R,S)-AHPC-C6-PEG3-C4-Cl

Background Introduction

(S,R,S)-AHPC-C6-PEG3-C4-Cl is a specialized E3 ligase ligand-linker conjugate, designed for use in the development of PROTACs (Proteolysis Targeting Chimeras) and targeted protein degradation technologies. The compound incorporates an optimized von Hippel-Lindau (VHL) ligand (AHPC) framework linked by a flexible PEG3-based linker, making it a versatile building block for innovative drug discovery and chemical biology research.

Mechanism

The mechanism of action for (S,R,S)-AHPC-C6-PEG3-C4-Cl centers on its role as an E3 ligase recruiter in PROTAC molecule design. The AHPC moiety binds selectively to the VHL E3 ubiquitin ligase complex, enabling the recruitment of the cellular degradation machinery. The PEG3-C6-C4 linker provides spatial flexibility for the conjugation of various target protein ligands via the terminal chloride group. Once a target ligand is attached and the final PROTAC is formed, it simultaneously engages the target protein and the VHL ligase, promoting ubiquitination and subsequent proteasomal degradation of the target protein.

Applications

(S,R,S)-AHPC-C6-PEG3-C4-Cl is widely used in medicinal chemistry and chemical biology research for the synthesis of PROTACs targeting diverse disease-relevant proteins. Its customizable linker and reactive chloride group enable the rapid development of bifunctional molecules for preclinical studies in oncology, neurology, and immunology. The product is particularly valuable for structure-activity relationship (SAR) studies, target validation, and the creation of next-generation protein degradation therapeutics, facilitating advances in drug discovery where traditional inhibitors may not suffice.

• Versatile PEGylated linker design improves solubility and pharmacokinetics in PROTAC development.
• AHPC-based ligand ensures high-affinity VHL E3 ligase recruitment, enabling efficient target protein degradation.

The E3 Ligase Ligand-Linker Conjugate, (S,R,S)-AHPC-C6-PEG3-C4-Cl, plays a crucial role in PROTAC technology by facilitating the targeted degradation of proteins. It combines an E3 ligase ligand and a linker, offering specificity and versatility. The following provides a detailed description of this molecule.

Linker: The linker in this molecule is a C6-PEG3-C4 chain, characterized by moderate length and flexibility due to the polyethylene glycol (PEG) units. This flexibility enhances the molecule's ability to adapt to various spatial conformations, while the cleavable C4 segment allows for controlled release of the active components.

Ligand: The ligand component is AHPC, a small molecule designed to bind effectively to the E3 ligase. Its stereochemistry, indicated by the (S,R,S) configuration, ensures high-affinity binding, which is crucial for the efficient recruitment of the E3 ligase to the target protein complex.

Reactive Site: The reactive site of the molecule is the terminal chloride (Cl) group, which is ideally positioned for coupling with the target protein ligand. Recommended reaction types include nucleophilic substitution reactions, where the chloride acts as a leaving group, facilitating covalent bond formation with the target protein ligand.

Recommended Target Protein Ligand: This molecule is compatible with electrophilic warheads that can efficiently form covalent bonds with nucleophilic sites on target proteins. The advantage of using such warheads lies in their ability to irreversibly modify the target, ensuring sustained degradation. This approach is particularly useful in applications where permanent inhibition of protein function is desired, such as in cancer research or neurodegenerative disease studies.