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

Background Introduction

(S,R,S)-AHPC-C8-NH2 is an advanced E3 ligase ligand-linker conjugate featuring the VHL (von Hippel-Lindau) ligand AHPC attached to an 8-carbon alkyl linker with a terminal amine group. This intermediate is a crucial building block in the synthesis of Proteolysis Targeting Chimeras (PROTACs), which are bifunctional molecules engineered to harness the cellular ubiquitin-proteasome system for targeted protein degradation. The modular design and synthetic accessibility of (S,R,S)-AHPC-C8-NH2 make it highly valuable for the rapid development of PROTAC libraries to address undruggable targets in drug discovery.

Mechanism

The (S,R,S)-AHPC-C8-NH2 functions by recruiting the Von Hippel-Lindau (VHL) E3 ubiquitin ligase to the proximity of a specific target protein through its conjugation with a suitable ligand. Upon hybridization with a target protein binder via the terminal amine, the final PROTAC molecule induces the formation of a ternary complex involving the E3 ligase, the target protein, and the PROTAC. This assembly facilitates the ubiquitination of the target protein, marking it for rapid degradation by the 26S proteasome. The C8 alkyl linker provides spatial flexibility and optimal orientation for efficient ternary complex formation and subsequent ubiquitination events.

Applications

(S,R,S)-AHPC-C8-NH2 serves as a versatile scaffold for developing VHL-based PROTACs aimed at selective protein degradation. Its terminal amine provides a convenient synthetic handle for coupling with a diverse range of target-binding ligands, enabling the generation of custom PROTACs for research and drug discovery. Key applications include: constructing screening libraries for high-throughput identification of degrader molecules; developing chemical probes for validating protein function; and generating lead compounds for therapeutic programs targeting oncogenic, neurodegenerative, or other disease-associated proteins. Additionally, (S,R,S)-AHPC-C8-NH2 is compatible with various conjugation chemistries, allowing researchers to streamline the production of next-generation PROTACs with enhanced selectivity and bioactivity.