(S,R,S)-AHPC-PEG2-azide

Background Introduction

(S,R,S)-AHPC-PEG2-azide is a versatile E3 ligase ligand-linker conjugate widely utilized in PROTAC (Proteolysis Targeting Chimera) technologies. Built around the potent Von Hippel-Lindau (VHL) E3 ligase ligand (AHPC), this molecule features a flexible PEG2 spacer and a terminal azide group. These structural elements enable precise bioconjugation via click chemistry, making it an essential building block for the construction of next-generation PROTAC molecules and other heterobifunctional degraders.

Mechanism

The mechanism of (S,R,S)-AHPC-PEG2-azide centers on targeted protein degradation through the ubiquitin-proteasome system. The AHPC moiety binds selectively to the VHL E3 ubiquitin ligase complex. The PEG2 linker increases solubility and provides optimal spatial arrangement, minimizing steric hindrance. The azide group at the terminus allows for efficient click chemistry conjugation with alkyne-functionalized ligands. In PROTAC assembly, the resultant chimera connects a target protein ligand to the E3 ligase ligand, bringing the target in close proximity to the E3 ligase and promoting ubiquitination and subsequent proteasomal degradation of the target protein.

Applications

(S,R,S)-AHPC-PEG2-azide is a premier tool in the design of PROTACs aimed at targeted protein degradation. It is valuable in preclinical research for developing and optimizing novel PROTAC molecules targeting disease-relevant proteins in oncology, neurodegeneration, and immunology. The azide functionality facilitates rapid prototyping through bio-orthogonal click chemistry, accelerating SAR (structure-activity relationship) studies and enabling the creation of chemical probes, dual-targeting degraders, and other protein homeostasis modulators. This conjugate is also applicable in PROTAC library synthesis, facilitating high-throughput screening of degraders with diverse target profiles.

• Azide-functionalized PEG2 linker enables versatile click chemistry conjugation for efficient PROTAC assembly.
• Designed for VHL-based PROTAC synthesis, offering high selectivity and improved cellular permeability.