(S,R,S)-AHPC-PEG2-NH2

Background Introduction

(S,R,S)-AHPC-PEG2-NH2 is a specialized E3 ligase ligand-linker conjugate designed for use in the development of proteolysis targeting chimeras (PROTACs). The molecule features the (S,R,S)-AHPC moiety, a high-affinity VHL E3 ligase ligand, conjugated to a short, hydrophilic PEG2 linker terminated with an amine group for efficient coupling with target protein ligands. This structure enables rapid and reliable assembly of custom PROTAC molecules for both in vitro and in vivo applications.

Mechanism

The mechanism of action for (S,R,S)-AHPC-PEG2-NH2 is rooted in the targeted protein degradation process facilitated by PROTAC technology. The (S,R,S)-AHPC moiety binds selectively to the Von Hippel-Lindau (VHL) E3 ubiquitin ligase, while the PEG2-NH2 linker serves as a flexible spacer for attachment to a ligand that recognizes the desired protein of interest. Once synthesized into a bifunctional PROTAC, the molecule brings the target protein into proximity with the VHL E3 ligase, leading to its ubiquitination and subsequent proteasomal degradation. The PEG2 linker ensures optimal spatial orientation and solubility, improving the PROTAC’s bioactivity and pharmacokinetic properties.

Applications

(S,R,S)-AHPC-PEG2-NH2 is widely employed in the design and synthesis of VHL-recruiting PROTACs for targeted protein degradation research. Its robust performance makes it ideal for projects aiming to elucidate disease-relevant protein functions, validate novel drug targets, and develop next-generation therapeutics in oncology, neurodegeneration, and immunology. This conjugate is also used in high-throughput screening assays, cell-based studies, and preclinical validation of PROTAC efficacy, streamlining the discovery and optimization of new chemical entities for drug development pipelines.

(S,R,S)-AHPC-PEG2-NH2 is a versatile E3 Ligase Ligand-Linker Conjugate used in the development of PROTACs for targeted protein degradation. This molecule integrates a strategically designed linker and ligand, facilitating efficient recruitment of E3 ligases to target protein complexes, enhancing degradation efficacy. The following provides a detailed description of this molecule.

Linker: The PEG2 linker in this conjugate is characterized by its short length and flexible nature, which enhances solubility and cellular permeability. Its non-cleavable design ensures stability within the cellular environment, maintaining the integrity of the PROTAC complex during the degradation process.

Ligand: The ligand component, based on (S,R,S)-AHPC, is a potent VHL E3 ligase binder. Its stereochemically optimized structure ensures high-affinity interaction with the E3 ligase, promoting efficient ubiquitination and subsequent proteasomal degradation of the target protein.

Reactive Site: The reactive amine group (NH2) in this molecule is designed for coupling with target protein ligands. Recommended reaction types include amide bond formation and reductive amination, which provide robust and stable linkages essential for effective PROTAC assembly.

Recommended Target Protein Ligand: The ideal warhead for this molecule is one that forms a covalent or non-covalent bond with the target protein, such as a kinase inhibitor. This selection enhances the specificity and potency of the PROTAC, facilitating the targeted degradation of proteins involved in critical cellular pathways, thus providing valuable insights for experimental studies.