(S,R,S)-AHPC-PEG3-N3

Background Introduction

(S,R,S)-AHPC-PEG3-N3 is a next-generation E3 ligase ligand-linker conjugate designed specifically for PROTAC (Proteolysis Targeting Chimera) and targeted protein degradation applications. Featuring an (S,R,S)-AHPC-based CRBN (cereblon) E3 ligase ligand, this compound is conjugated via a PEG3 (triethylene glycol) spacer to an azide (N3) functional group, providing both biocompatibility and enhanced solubility. The azido group enables rapid and reliable click chemistry-mediated conjugation to various target protein ligands, paving the way for efficient, modular PROTAC development.

Mechanism

(S,R,S)-AHPC-PEG3-N3 operates by binding selectively to the cereblon E3 ubiquitin ligase through its (S,R,S)-AHPC motif. The PEG3 linker offers ideal flexibility and reduced steric hindrance, improving both cellular permeability and solubility of the final PROTAC construct. The azide group at the terminal end of the linker allows for facile conjugation to alkyne-modified ligands or biomolecules via copper-catalyzed azide-alkyne cycloaddition (CuAAC, 'click chemistry'). Once assembled into a bifunctional PROTAC molecule, it bridges the target protein and cereblon E3 ligase, facilitating ubiquitination and subsequent proteasomal degradation of the target protein.

Applications

(S,R,S)-AHPC-PEG3-N3 is ideally suited for the development of novel PROTACs, molecular glue degraders, and related targeted protein degradation therapies. Researchers can utilize this compound's click-ready azide functionality for customizable and high-throughput library generation of protein degraders. It is widely employed in drug discovery and chemical biology studies aimed at validating new therapeutic targets or rapidly optimizing PROTAC constructs. Its application extends to in vitro, cellular, and animal model studies for understanding disease biology and leveraging targeted protein degradation as a therapeutic strategy.