(S,R,S)-AHPC-PEG2-Alkyne

Background Introduction

(S,R,S)-AHPC-PEG2-Alkyne is a specialized E3 ligase ligand-linker conjugate designed for use in targeted protein degradation research and drug discovery. Based on the small molecule AHPC, a highly selective ligand for the VHL (von Hippel-Lindau) E3 ligase, this tool compound features a PEG2 spacer and an alkyne functional group, making it highly versatile for constructing novel PROTACs (Proteolysis Targeting Chimeras) via click chemistry. Tailored for superior solubility and reactivity, (S,R,S)-AHPC-PEG2-Alkyne is a valuable asset for researchers developing next-generation therapeutics targeting disease-relevant proteins.

Mechanism

(S,R,S)-AHPC-PEG2-Alkyne functions as an E3 ligase recruiting moiety in PROTAC technology. When incorporated into a PROTAC molecule, the AHPC unit binds specifically to the VHL E3 ubiquitin ligase complex. The PEG2 linker adds flexibility and optimal spatial orientation, while the alkyne group enables efficient conjugation to a wide range of target protein ligands using click chemistry. Upon successful recruitment, the resultant PROTAC molecule brings the VHL ligase and the protein of interest into close proximity, facilitating ubiquitination and subsequent degradation of the target protein via the proteasome pathway.

Applications

(S,R,S)-AHPC-PEG2-Alkyne is widely employed in the design and synthesis of custom PROTACs for protein degradation studies. Its alkyne handle allows for modular assembly with different target ligands, accelerating the development of PROTAC libraries for target validation and early-stage drug discovery. Common research applications include the generation of VHL-based PROTACs for oncology, neurodegenerative disease, and immunological disorder research. Its versatility also makes it suitable for live-cell degradation assays, mechanistic studies, and structure-activity relationship (SAR) exploration. By enabling selective degradation of disease-related proteins, (S,R,S)-AHPC-PEG2-Alkyne contributes substantially to advancing targeted protein degradation as a therapeutic strategy.

• Alkyne-modified PEG2 linker enables efficient and versatile click chemistry for rapid PROTAC assembly.
• High affinity for VHL E3 ligase, ensuring potent and selective protein degradation in targeted therapies.

(S,R,S)-AHPC-PEG2-Alkyne is a versatile E3 Ligase Ligand-Linker Conjugate designed for the development of PROTACs, facilitating targeted protein degradation. This compound features a sophisticated linker and ligand system, enhancing binding specificity and efficacy. The following provides a detailed description of this molecule's linker, ligand, and selection of target protein ligands.

Linker: The linker in (S,R,S)-AHPC-PEG2-Alkyne is a PEG2 chain, offering moderate flexibility and optimal length for efficient spatial accommodation between the ligand and target protein. Its non-cleavable nature ensures stability, making it suitable for sustained interactions in cellular environments.

Ligand: The ligand component is based on AHPC, a derivative of thalidomide, known for its high affinity to the CRBN E3 ligase. Its stereochemistry, denoted as (S,R,S), enhances specificity and binding affinity, crucial for effective PROTAC formation and function.

Reactive Site: The alkyne moiety serves as the reactive site, designed to couple with azide-functionalized target protein ligands through a copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. This "click chemistry" approach is favored for its efficiency and robustness in bioconjugation processes.

Recommended Target Protein Ligand: An azide-functionalized warhead is recommended for compatibility with the alkyne group in (S,R,S)-AHPC-PEG2-Alkyne. Such warheads enable efficient CuAAC reactions, facilitating the formation of stable triazole linkages. This approach is advantageous for creating highly specific and potent PROTACs, applicable in diverse research settings to study protein degradation pathways.