(S,R,S)-AHPC-phenol-alkylC6-amine dihydrochloride

Background Introduction

(S,R,S)-AHPC-phenol-alkylC6-amine dihydrochloride is a specialized E3 ligase ligand-linker conjugate designed for use in PROTAC (Proteolysis Targeting Chimera) technology. Built upon the AHPC scaffold—a potent binder of the von Hippel-Lindau (VHL) E3 ligase—this molecule features a phenol group and a six-carbon alkyl amine linker, facilitating flexible tethering to various warhead ligands. Its dihydrochloride salt form ensures improved solubility and suitability for chemical biology applications.

Mechanism

The mechanism of (S,R,S)-AHPC-phenol-alkylC6-amine dihydrochloride centers on its ability to recruit the VHL E3 ubiquitin ligase through its AHPC core. The phenol-alkylC6-amine linker terminus is designed for conjugation to ligands that bind a target protein of interest. When incorporated into a PROTAC construct, this ligand-linker conjugate bridges the E3 ligase and the target protein, facilitating the formation of a ternary complex. This proximity promotes ubiquitination of the target protein, which is then recognized and degraded by the proteasome, leading to selective protein knockdown within cells.

Applications

(S,R,S)-AHPC-phenol-alkylC6-amine dihydrochloride is widely applied in the design and synthesis of custom PROTAC molecules. Researchers use this conjugate for rapid assembly of heterobifunctional degraders targeting diverse disease-related proteins, especially in cancer, neurodegeneration, and immunology research. Its modular structure enables efficient exploration of linker length and orientation effects in PROTAC optimization campaigns. The compound is also valuable in structure-activity relationship (SAR) studies and mechanism-based drug discovery, accelerating the development of next-generation targeted protein degradation therapeutics.

• Versatile amine-functionalized linker ideal for efficient E3 ligase ligand conjugation in PROTAC synthesis.
• Optimized for VHL-based PROTAC design, offering reliable performance in targeted protein degradation applications.

The (S,R,S)-AHPC-phenol-alkylC6-amine dihydrochloride serves as a versatile E3 Ligase Ligand-Linker Conjugate in PROTACs, facilitating targeted protein degradation by bridging E3 ligase and target proteins. This molecule's components, including its linker, ligand, and reactive site, are designed to optimize degradation efficiency and selectivity for research applications. The following provides a detailed description of this molecule.

Linker: The linker in this molecule is an alkyl chain of six carbon atoms, offering moderate flexibility and non-cleavable characteristics. This design ensures optimal spatial arrangement and stability, enhancing the conjugate's ability to effectively engage with its target proteins.

Ligand: The ligand component is based on AHPC, a derivative known for its specificity in binding to E3 ligases. Its structural characteristics include a phenol moiety, which contributes to its binding affinity and selectivity, ensuring efficient recruitment of the E3 ligase.

Reactive Site: The reactive site comprises an amine group that facilitates coupling with the target protein ligand. Recommended reaction types include amide bond formation or reductive amination, which are robust and efficient for forming stable conjugates.

Recommended Target Protein Ligand: A suitable warhead for this conjugate is a small molecule with an electrophilic group, such as an acrylamide or chloroacetamide. These warheads offer high reactivity and selectivity, making them ideal for covalent modification of cysteine residues on target proteins, thereby enhancing the specificity and efficacy of the PROTAC.