(S,R,S)-AHPC-CO-C8-ACID

Background Introduction

(S,R,S)-AHPC-CO-C8-ACID is an advanced E3 ligase ligand-linker conjugate used widely in the field of targeted protein degradation. As a derivative of AHPC (aryl hydroxyproline carboxylate), this compound is designed to serve as an essential building block for the development of PROTACs (Proteolysis Targeting Chimeras). By integrating a medium-chain alkyl (C8) acid linker, (S,R,S)-AHPC-CO-C8-ACID offers enhanced flexibility and optimal spacing for efficient PROTAC construction, helping researchers drive cutting-edge studies in chemical biology and drug discovery.

Mechanism

The core mechanism of (S,R,S)-AHPC-CO-C8-ACID lies in its ability to recruit the E3 ubiquitin ligase complex, particularly the Von Hippel-Lindau (VHL) ligase, by acting as a high-affinity ligand. The compound’s C8 linker provides versatile conjugation points for attaching target protein ligands or other molecular entities. As part of a bifunctional PROTAC molecule, (S,R,S)-AHPC-CO-C8-ACID brings the target protein into close proximity with the E3 ligase, facilitating ubiquitination of the target protein. This ubiquitinated protein is then recognized and degraded by the proteasome, enabling selective and catalytic protein knockdown within cells.

Applications

(S,R,S)-AHPC-CO-C8-ACID is primarily used in the synthesis of VHL-based PROTACs for targeted protein degradation. Its applications span across oncology, neurodegenerative diseases, and other therapeutic areas where pathological proteins need to be selectively depleted. This E3 ligase ligand-linker conjugate is invaluable for medicinal chemistry research, high-throughput screening, target validation studies, and the development of next-generation therapeutics. Additionally, it supports structure-activity relationship (SAR) exploration by providing a modular linker, enabling researchers to optimize PROTAC efficacy and selectivity.

• Long aliphatic C8 linker optimizes spatial flexibility for efficient VHL E3 ligase recruitment in PROTAC design.
• Carboxylic acid functional group enables versatile conjugation with diverse warheads, facilitating custom PROTAC synthesis.

The E3 Ligase Ligand-Linker Conjugate (S,R,S)-AHPC-CO-C8-ACID plays a pivotal role in the development of PROTACs by facilitating targeted protein degradation. This conjugate combines a ligand for E3 ligase binding with a linker that connects to a target protein ligand, offering versatility in protein degradation strategies. The following provides a detailed description of this molecule.

Linker: The linker in this molecule is an eight-carbon chain, providing moderate length and flexibility, which is crucial for accommodating spatial requirements between the ligand and the target protein. Its non-cleavable nature ensures stability and consistent performance in degradation assays.

Ligand: The ligand is derived from AHPC, a small molecule that effectively binds to the VHL E3 ligase. Its stereochemistry (S,R,S) is optimized for high-affinity interaction, ensuring efficient recruitment of the E3 ligase to the target protein.

Reactive Site: The reactive site is a carboxylic acid group at the terminus of the linker, designed for coupling with amine-functionalized target protein ligands. Recommended reaction types include amide bond formation through carbodiimide-mediated coupling or click chemistry for efficient conjugation.

Recommended Target Protein Ligand: The compatible warhead for this molecule is an amine-containing ligand, which can form stable amide bonds with the carboxylic acid reactive site. This configuration is advantageous for targeting proteins with accessible lysine residues, facilitating precise degradation in cellular environments and enabling the study of protein function and regulation.