(S,R,S)-AHPC-C8-NH2 dihydrochloride

Background Introduction

(S,R,S)-AHPC-C8-NH2 dihydrochloride is a specialized E3 ligase ligand-linker conjugate designed for use in the development of proteolysis targeting chimeras (PROTACs). PROTAC technology leverages the ubiquitin-proteasome system for targeted protein degradation, and the choice of an effective E3 ligase ligand is essential for the creation of potent and selective PROTAC molecules.

Mechanism

(S,R,S)-AHPC-C8-NH2 dihydrochloride functions as a selective ligand for the von Hippel-Lindau (VHL) E3 ubiquitin ligase. This compound features an (S,R,S)-configured AHPC (hydroxyproline-based) core tethered to an 8-carbon alkyl linker terminated with a primary amine, allowing for conjugation to target protein ligands. When incorporated into a PROTAC, the E3 ligase ligand-linker conjugate bridges the E3 ligase and the protein of interest, inducing proximity that facilitates ubiquitination and subsequent proteasomal degradation of the target protein.

Applications

(S,R,S)-AHPC-C8-NH2 dihydrochloride is widely used in the design and synthesis of VHL-based PROTACs for targeted protein degradation studies. This molecule enables researchers to develop custom PROTACs for the selective elimination of disease-related proteins, supporting investigation of protein function, validation of therapeutic targets, and preclinical drug discovery. Additionally, it serves as a valuable tool for optimizing linker length, facilitating structure-activity relationship studies, and expanding the repertoire of degraders for challenging drug targets in oncology, neurodegeneration, and immunology research.

• Extended C8 linker provides optimal spatial flexibility for VHL-based PROTAC design, facilitating efficient target protein degradation.
• Amine functional group ensures convenient conjugation with diverse ligands, streamlining the synthesis of custom PROTAC molecules.

The (S,R,S)-AHPC-C8-NH2 dihydrochloride is a versatile E3 Ligase Ligand-Linker Conjugate designed for use in PROTACs, facilitating targeted protein degradation. This molecule effectively bridges the E3 ligase and target protein, enhancing specificity and degradation efficiency. The following provides a detailed description of this molecule's linker, ligand, and selection of target protein ligands.

Linker: The linker in this molecule is an eight-carbon chain that offers a balance between flexibility and rigidity, optimizing spatial orientation for effective E3 ligase and target protein interaction. Its non-cleavable nature ensures stability throughout the degradation process.

Ligand: The ligand component is an AHPC moiety, known for its high affinity towards E3 ligases like cereblon. Its stereochemistry, specifically the (S,R,S) configuration, enhances binding specificity and efficiency, making it a crucial element in the PROTAC design.

Reactive Site: The primary reactive site is the terminal amine group, which readily couples with carboxyl or activated ester groups on the target protein ligand. Recommended reaction types include amide bond formation via EDC/NHS coupling, ensuring robust and stable conjugation.

Recommended Target Protein Ligand: A suitable warhead for this molecule is a small-molecule inhibitor possessing a carboxyl group for efficient coupling. This choice allows for effective target engagement and degradation, particularly in studies aiming to explore protein function or validate therapeutic targets. Researchers can leverage this system to investigate protein dynamics and cellular pathways with precision.