(S,R,S)-AHPC-phenol-C4-NH2 dihydrochloride

Background Introduction

(S,R,S)-AHPC-phenol-C4-NH2 dihydrochloride is an advanced E3 ligase ligand-linker conjugate, widely used in targeted protein degradation research, especially within the PROTAC (Proteolysis Targeting Chimera) field. AHPC is a well-established ligand for the Von Hippel-Lindau (VHL) E3 ubiquitin ligase, and the incorporation of a C4 amino linker enables it to be efficiently conjugated with various protein-targeting warheads.

Mechanism

This compound operates as a bifunctional molecule, featuring a high-affinity VHL E3 ligase ligand (AHPC) connected to a flexible C4 linker with a terminal amine group. In PROTAC design, (S,R,S)-AHPC-phenol-C4-NH2 serves as the E3 ligase-recruiting component. When chemically linked to a target protein binder via its amino moiety, it enables the formation of a heterobifunctional PROTAC. Upon cellular entry, the resulting PROTAC induces proximity between the target protein and the VHL E3 ligase, promoting ubiquitination and subsequent proteasomal degradation of the target protein. The dihydrochloride salt enhances solubility and stability for biochemical applications.

Applications

(S,R,S)-AHPC-phenol-C4-NH2 dihydrochloride finds broad use in the construction of VHL-based PROTACs for selective and robust degradation of disease-related proteins. Key applications include: development of chemical probes for target validation, pharmaceutical research for drug discovery and lead optimization, and academic studies exploring novel protein degradation pathways. Its amine-functionalized linker allows easy conjugation with various target-binding molecules, supporting the efficient design and synthesis of customized PROTACs for oncology, neurodegenerative diseases, and epigenetic research.

The (S,R,S)-AHPC-phenol-C4-NH2 dihydrochloride serves as an essential E3 Ligase Ligand-Linker Conjugate in PROTACs, facilitating targeted protein degradation by linking E3 ligases to target proteins, enhancing specificity and efficiency. The following provides a detailed description of this molecule, emphasizing its linker, ligand, and reactive site characteristics.

Linker: The linker in this molecule is a C4 alkyl chain, offering moderate flexibility and a non-cleavable nature, which ensures stability during the degradation process. Its length is optimal for maintaining the spatial orientation necessary for effective binding between the E3 ligase and the target protein.

Ligand: The ligand component, AHPC, is a derivative of thalidomide, known for its structural capability to bind selectively to cereblon, a component of the E3 ubiquitin ligase complex. This ensures precise recruitment of the ligase to the target protein, enhancing degradation efficiency.

Reactive Site: The reactive site features an amine group, which couples efficiently with electrophilic groups on target protein ligands. Recommended reaction types include amide bond formation and nucleophilic substitution, facilitating robust and stable conjugation.

Recommended Target Protein Ligand: The compatible warhead for this molecule is typically an electrophilic moiety, such as an acrylamide group, which forms covalent bonds with nucleophilic residues on target proteins. This approach is advantageous for achieving irreversible binding, thereby ensuring sustained target protein degradation. Such warheads are ideal for applications requiring long-lasting effects in cellular environments.