(S,R,S)-AHPC-PEG1-NH2 dihydrochloride

Background Introduction

(S,R,S)-AHPC-PEG1-NH2 dihydrochloride is a specially designed E3 ligase ligand-linker conjugate tailored for targeted protein degradation research. As a building block for PROTAC (Proteolysis Targeting Chimera) synthesis, this molecule features the von Hippel-Lindau (VHL) ligand (AHPC) coupled to an amino-terminated polyethylene glycol (PEG1) linker, presented in its dihydrochloride salt form to enhance solubility and stability. This unique structure allows researchers to efficiently couple the ligand to various protein-targeting moieties, facilitating custom PROTAC development for chemical biology and drug discovery applications.

Mechanism

The mechanism of (S,R,S)-AHPC-PEG1-NH2 dihydrochloride centers on its role as a modular E3 ligase recruiting unit in PROTAC design. The AHPC fragment specifically binds to the VHL E3 ubiquitin ligase complex, while the PEG1 linker enables flexible attachment to a ligand for the protein of interest. When assembled into a complete PROTAC molecule, the VHL-recruiting AHPC moiety brings the E3 ligase into close proximity with the target protein. This proximity promotes ubiquitination and subsequent proteasomal degradation of the target. The NH2 terminus of the linker provides convenient chemical functionality for conjugation to a variety of warheads or protein binding modules.

Applications

(S,R,S)-AHPC-PEG1-NH2 dihydrochloride is widely applied in the design and synthesis of PROTACs for both basic research and drug discovery. Its primary use is as an E3 ligase recruiting element, allowing researchers to target disease-relevant proteins for degradation via the ubiquitin-proteasome system. This conjugate is ideal for rapid structure-activity relationship (SAR) studies, exploration of novel protein degradation targets, and development of next-generation therapeutics for cancer, neurodegenerative diseases, and autoimmune conditions. The ready-to-use PEG1 linker enhances solubility and cellular permeability, making it a versatile platform for chemical biology, medicinal chemistry, and targeted protein degradation studies.

• Versatile PEG1 linker increases solubility and flexibility in PROTAC design, enabling more efficient protein degradation.
• Amine-terminated structure allows straightforward conjugation to diverse warheads, streamlining von Hippel-Lindau (VHL)-based PROTAC synthesis.