(S,R,S)-AHPC-PEG5-COOH

Background Introduction

(S,R,S)-AHPC-PEG5-COOH is a specialized E3 ligase ligand-linker conjugate commonly used in the design and synthesis of Proteolysis Targeting Chimeras (PROTACs). This compound seamlessly bridges the von Hippel-Lindau (VHL) E3 ligase ligand (derived from AHPC) with a customizable linker (PEG5) and a terminal carboxylic acid, enabling high flexibility for conjugation with target protein ligands in next-generation drug discovery.

Mechanism

As a bifunctional molecule, (S,R,S)-AHPC-PEG5-COOH facilitates targeted protein degradation through the PROTAC technology platform. The AHPC moiety selectively binds the VHL E3 ubiquitin ligase complex, while the PEG5 spacer provides optimal distance, solubility, and flexibility. The terminal COOH group enables straightforward coupling with a ligand for the protein of interest. When used in a full PROTAC construct, it brings the E3 ligase into proximity with the target protein, promoting ubiquitination and subsequent proteasomal degradation.

Applications

(S,R,S)-AHPC-PEG5-COOH is widely employed in the development of PROTACs for targeted protein degradation research, lead discovery, and validation studies. This reagent is essential in oncology, neurodegeneration, and immunology projects, where selective removal of disease-relevant proteins is desired. Its ready-to-use functionality accelerates the exploration of novel degraders in both academic and pharmaceutical research, making it a crucial tool for custom PROTAC synthesis, structure-activity relationship (SAR) studies, and therapeutic development.

• Long PEG5 linker increases PROTAC solubility and cellular permeability, optimizing drug-like properties.
• Carboxyl functional group enables versatile conjugation with diverse warheads for efficient VHL-based PROTAC assembly.

The (S,R,S)-AHPC-PEG5-COOH is a versatile E3 Ligase Ligand-Linker Conjugate designed for use in PROTACs, enhancing targeted protein degradation by facilitating precise interaction between the E3 ligase and the target protein. The following provides a detailed description of this molecule, focusing on its linker, ligand, and recommended target protein ligands.

Linker: The linker in (S,R,S)-AHPC-PEG5-COOH is a PEG5 chain, which offers a moderate length and flexible structure, enhancing solubility and bioavailability. Its non-cleavable nature ensures stability in biological environments, making it suitable for sustained interactions.

Ligand: The ligand component of this molecule is an (S,R,S)-AHPC moiety, characterized by its stereochemically defined structure. This ligand is known for its high affinity and specificity towards the VHL E3 ligase, facilitating efficient recruitment in the PROTAC complex.

Reactive Site: The reactive site is the terminal carboxylic acid group (COOH), which couples with target protein ligands through amide bond formation. Recommended reaction types include amide coupling reactions, such as using carbodiimide-based chemistry for efficient conjugation.

Recommended Target Protein Ligand: Compatible warheads for (S,R,S)-AHPC-PEG5-COOH include electrophilic groups capable of forming covalent bonds with nucleophilic residues on the target protein. These warheads enhance the specificity and efficacy of the PROTAC, allowing for precise degradation of disease-relevant proteins, and are particularly useful in cancer research and drug discovery applications.