(S,R,S)-AHPC-C6-NH2 dihydrochloride

Background Introduction

(S,R,S)-AHPC-C6-NH2 dihydrochloride is a specialized E3 ligase ligand-linker conjugate widely utilized in the development of PROTACs (Proteolysis Targeting Chimeras). As a derivative of the well-characterized AHPC (aryl hydroxyproline carboxamide), it is engineered to recruit the von Hippel-Lindau (VHL) E3 ligase, a key player in ubiquitin-mediated protein degradation. The compound features a flexible hexyl (C6) linker terminated with an amino (NH2) group, optimized for efficient conjugation to target-binding ligands.

Mechanism

(S,R,S)-AHPC-C6-NH2 dihydrochloride functions as a bifunctional building block in PROTAC design. The AHPC moiety selectively binds to the VHL E3 ubiquitin ligase complex, while the C6-NH2 linker enables straightforward attachment to small molecule ligands or peptides specific for the protein of interest. Upon cellular delivery, PROTAC molecules incorporating this conjugate simultaneously engage the target protein and VHL ligase, facilitating the formation of a ternary complex. This proximity triggers ubiquitination and subsequent proteasomal degradation of the target protein, allowing for precise and catalytic removal of disease-associated proteins.

Applications

This VHL ligand-linker conjugate is essential for researchers in drug discovery and chemical biology aiming to create novel PROTACs. Its primary applications include the synthesis of customized PROTAC molecules targeting various disease-associated proteins, especially oncogenic and pathogenic proteins resistant to traditional small molecule inhibitors. (S,R,S)-AHPC-C6-NH2 dihydrochloride is widely used for target validation studies, mechanistic research in targeted protein degradation, and development of next-generation therapeutics in oncology, neurodegeneration, and immunology, offering powerful tools for modulating previously undruggable proteins.

• Amine-terminated C6 linker ensures versatile and stable conjugation with target ligands, optimizing the assembly of potent PROTAC molecules.
• Highly selective VHL E3 ligase recruiter, facilitating efficient ubiquitination and targeted protein degradation applications.

The (S,R,S)-AHPC-C6-NH2 dihydrochloride serves as a versatile E3 Ligase Ligand-Linker Conjugate in the design of PROTACs, facilitating targeted protein degradation by bridging E3 ubiquitin ligases with target proteins. The following provides a detailed description of this molecule's linker, ligand, and reactive site characteristics.

Linker: This molecule features a six-carbon aliphatic linker, providing moderate flexibility to accommodate diverse spatial orientations. Its non-cleavable nature ensures stable conjugation between the ligand and the target protein, optimizing the efficiency of the degradation process.

Ligand: The ligand in this structure is based on AHPC, a derivative known for its high affinity and specificity towards the VHL E3 ubiquitin ligase. Its stereochemistry enhances binding efficiency, ensuring robust and selective protein degradation.

Reactive Site: The reactive site of this molecule is the primary amine, which is strategically positioned to couple with a variety of electrophilic moieties on target protein ligands. Recommended reaction types include amide coupling or urea formation, which facilitate stable conjugate formation.

Recommended Target Protein Ligand: Compatible warheads for this conjugate include electrophilic groups such as acrylamides or chloroacetamides, which efficiently form covalent bonds with nucleophilic residues on target proteins. These warheads are advantageous for their ability to form irreversible bonds, enhancing the selectivity and potency of the resulting PROTACs in experimental studies.