(S,R,S)-AHPC-PEG6-Alkyne

Background Introduction

(S,R,S)-AHPC-PEG6-Alkyne is a versatile E3 ligase ligand-linker conjugate designed for advanced protein degradation technologies, notably PROTACs (Proteolysis Targeting Chimeras). It incorporates (S,R,S)-AHPC, a high-affinity ligand for the von Hippel-Lindau (VHL) E3 ubiquitin ligase complex, connected via a PEG6 (polyethylene glycol, 6 units) linker to an alkyne functional group. This flexible and reactive scaffold is ideal for chemical conjugation, enabling the development of novel PROTAC molecules targeting disease-relevant proteins.

Mechanism

(S,R,S)-AHPC-PEG6-Alkyne functions by leveraging the body's ubiquitin-proteasome system. The (S,R,S)-AHPC moiety selectively recruits the VHL E3 ligase complex, while the PEG6 linker provides an optimal spatial arrangement for target engagement. The alkyne group allows for bioorthogonal 'click chemistry', enabling attachment to a variety of target protein ligands or small molecules. Once the conjugate brings the E3 ligase and the protein of interest into proximity, ubiquitination is triggered, leading to proteasomal degradation of the target protein.

Applications

This E3 ligase ligand-linker conjugate is primarily utilized in the synthesis of custom PROTACs for target protein degradation. Its alkyne handle enables modular assembly with azide-functionalized compounds via copper-catalyzed azide-alkyne cycloaddition (CuAAC). Researchers employ (S,R,S)-AHPC-PEG6-Alkyne for structure-activity relationship (SAR) studies, target validation, and therapeutic discovery in oncology, neurodegeneration, and immunology. This product supports rapid prototyping and optimization of bifunctional degraders for both in vitro and in vivo applications.

• PEG6 spacer increases solubility and cellular permeability for enhanced PROTAC performance.
• Alkyne functional group enables versatile click chemistry, streamlining E3 ligase ligand conjugation in targeted protein degradation applications.

The (S,R,S)-AHPC-PEG6-Alkyne is an E3 Ligase Ligand-Linker Conjugate designed for use in PROTAC technology, facilitating targeted protein degradation by linking an E3 ligase ligand to a target protein ligand. The following provides a detailed description of this molecule, focusing on its linker, ligand, and reactive site characteristics.

Linker: The PEG6 linker in this molecule is a polyethylene glycol chain with six ethylene glycol units, offering moderate flexibility and hydrophilicity. Its length is optimal for bridging the E3 ligase and target protein, ensuring effective proximity for ubiquitination. The linker is non-cleavable, maintaining structural integrity during the degradation process.

Ligand: The ligand component is an (S,R,S)-AHPC moiety, a derivative of thalidomide that effectively binds to the cereblon E3 ligase. Its stereochemistry is crucial for high-affinity interactions, ensuring efficient recruitment of the E3 ligase to the target protein complex.

Reactive Site: The alkyne functional group serves as the reactive site, allowing for bioorthogonal click chemistry reactions with azide-functionalized target protein ligands. This site is ideal for copper-catalyzed azide-alkyne cycloaddition (CuAAC), facilitating covalent conjugation under mild conditions.

Recommended Target Protein Ligand: Azide-functionalized warheads are compatible with this molecule, offering specificity and reactivity through click chemistry. These warheads enable precise conjugation with the alkyne group, enhancing the selectivity of the PROTAC for its target protein. Applications include the degradation of proteins involved in disease pathways, aiding in the elucidation of protein function and potential therapeutic interventions.