(S,R,S)-AHPC-C2-NH2 dihydrochloride

Background Introduction

(S,R,S)-AHPC-C2-NH2 dihydrochloride is a versatile E3 ligase ligand-linker conjugate designed specifically for PROTAC (Proteolysis Targeting Chimera) technology. By incorporating the AHPC (aryl hydroxyproline carboxamide) moiety, this molecule efficiently recruits the von Hippel-Lindau (VHL) E3 ubiquitin ligase, enabling targeted protein degradation. As a functionalized warhead with a reactive amine group and a dihydrochloride salt for enhanced solubility, (S,R,S)-AHPC-C2-NH2 serves as an essential building block in next-generation drug discovery research and targeted protein degradation applications.

Mechanism

The mechanism of (S,R,S)-AHPC-C2-NH2 dihydrochloride centers on its role as the E3 ligase-binding arm in bifunctional PROTAC molecules. The AHPC motif selectively binds to the VHL E3 ligase complex, while the C2-linked primary amine provides a handle for conjugating target protein ligands via amide bond formation. Upon cellular entry, PROTACs constructed with (S,R,S)-AHPC-C2-NH2 bring the E3 ligase and target protein into proximity. This facilitates ubiquitination and proteasomal degradation of the target, driving potent and selective protein knockdown.

Applications

(S,R,S)-AHPC-C2-NH2 dihydrochloride is widely used in the custom synthesis of PROTAC molecules for targeted protein degradation studies. Its applications span early-stage drug discovery, functional genomics, and validation of novel drug targets. Scientists use this ligand-linker conjugate to streamline the development of PROTAC libraries against disease-associated proteins, enabling rapid screening and structure-activity relationship (SAR) exploration. Its reliable E3 ligase recruitment makes it highly valuable for both academic research and pharmaceutical development in the emerging field of targeted protein degradation.

The (S,R,S)-AHPC-C2-NH2 dihydrochloride is a versatile E3 Ligase Ligand-Linker Conjugate that plays a crucial role in PROTACs, facilitating targeted protein degradation by bridging specific E3 ligases and target proteins. This molecule enhances the precision and efficacy of protein degradation, offering a robust platform for research into selective protein modulation. The following provides a detailed description of this molecule.

Linker: The linker in this molecule is a C2 alkyl chain, providing a moderate length that balances flexibility and rigidity. Its non-cleavable nature ensures stability during the degradation process, maintaining the integrity of the conjugate for effective E3 ligase recruitment.

Ligand: The ligand component of this molecule is based on AHPC, a derivative known for its high affinity and specificity towards the von Hippel-Lindau (VHL) E3 ligase. It features a chiral center, contributing to its selective binding capabilities and enhancing the overall efficacy of the PROTAC.

Reactive Site: The reactive site is an amine group (NH2) that facilitates coupling with the target protein ligand. Recommended reaction types include amide bond formation or urea linkage, offering robust and stable connections for efficient target engagement.

Recommended Target Protein Ligand: The compatible warhead for this molecule is typically an electrophilic moiety, such as a carbonyl-containing group, which can form covalent bonds with nucleophilic residues on the target protein. This approach enhances the selectivity and potency of the PROTAC, making it ideal for experimental studies focused on degrading disease-related proteins.