(S,R,S)-AHPC-PEG5-NH2 hydrochloride

Background Introduction

(S,R,S)-AHPC-PEG5-NH2 hydrochloride is a high-purity E3 ligase ligand-linker conjugate designed specifically for targeted protein degradation research. This versatile building block is a derivative of (S,R,S)-AHPC (aryl hydrocarbon receptor-interacting protein/hydroxyproline-conjugated), a potent ligand for the von Hippel-Lindau (VHL) E3 ubiquitin ligase, and incorporates a PEG5 (pentaethylene glycol) linker with a terminal amine functional group. The hydrochloride salt form guarantees enhanced solubility and stability, making it an ideal tool for constructing highly efficient PROTAC (Proteolysis Targeting Chimera) molecules.

Mechanism

(S,R,S)-AHPC-PEG5-NH2 hydrochloride functions by bridging a target protein and the cellular ubiquitination machinery via the VHL E3 ligase. The (S,R,S)-AHPC moiety selectively binds to VHL, while the PEG5 linker provides optimal spatial flexibility and improves solubility. The terminal amine enables facile conjugation to various target ligands or pharmacophores. In PROTAC applications, this conjugate is covalently attached to a ligand that recognizes a protein of interest, forming a bifunctional molecule. The resultant PROTAC simultaneously recruits VHL and the target protein into proximity, leading to target ubiquitination and subsequent proteasomal degradation.

Applications

(S,R,S)-AHPC-PEG5-NH2 hydrochloride is widely used in the development and optimization of PROTACs for chemical biology and drug discovery. It enables the rapid assembly of new PROTAC molecules targeting challenging or "undruggable" proteins implicated in cancer, neurodegenerative disorders, and other diseases. Researchers employ this reagent for early-stage screening, structure-activity relationship (SAR) studies, and proof-of-concept degradation experiments. Additionally, its PEG5 linker enhances pharmacokinetics and cellular permeability of final PROTAC molecules, making it a valuable asset in preclinical therapeutic development and mechanistic studies of targeted protein degradation.

• High-affinity VHL ligand ensures effective recruitment of E3 ubiquitin ligase for targeted protein degradation.
• PEG5 linker enhances aqueous solubility and improves pharmacokinetic properties for advanced PROTAC development.

The E3 Ligase Ligand-Linker Conjugate, (S,R,S)-AHPC-PEG5-NH2 hydrochloride, plays a crucial role in the development of PROTACs by facilitating targeted protein degradation. This compound offers significant advantages, including enhanced specificity and efficacy in protein degradation applications. The following provides a detailed description of this molecule, focusing on its linker, ligand, and reactive site characteristics.

Linker: The linker in this molecule is a PEG5 chain, characterized by its moderate length and flexible nature, which allows for optimal spatial arrangement between the ligand and the target protein. This flexibility enhances the molecule's ability to reach and bind target proteins effectively. The linker is non-cleavable, providing stability to the conjugate.

Ligand: The ligand component is based on a thalidomide derivative, known for its high affinity and specificity towards the CRBN E3 ligase. The stereochemistry of the ligand, denoted by (S,R,S), ensures precise molecular recognition and binding, which is crucial for the successful recruitment of the E3 ligase.

Reactive Site: The reactive site of this molecule is the terminal amine group, which is well-suited for coupling with target protein ligands through amide bond formation or reductive amination. These reaction types are recommended for their efficiency and stability in forming the desired conjugate.

Recommended Target Protein Ligand: The compatible warhead for this molecule is typically a small-molecule inhibitor or binder of the target protein, featuring a functional group that can form a stable covalent bond with the reactive amine. This approach leverages the advantages of selective protein degradation, enabling researchers to investigate protein function and validate therapeutic targets in various biological contexts.