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

Background Introduction

(S,R,S)-AHPC-PEG1-NH2 hydrochloride is a versatile E3 ligase ligand-linker conjugate based on the AHPC (3-amino-2-hydroxy-4-phenylbutanoic acid) scaffold. It is designed to facilitate targeted protein degradation through the proteolysis targeting chimera (PROTAC) approach. The incorporation of a hydrophilic PEG1 linker and terminal amine functionality enables convenient conjugation to various target-binding ligands, making this compound an essential building block for rational PROTAC design.

Mechanism

(S,R,S)-AHPC-PEG1-NH2 hydrochloride operates as a cereblon (CRBN) E3 ligase ligand. When covalently linked via the PEG1 spacer to a ligand that binds a protein of interest, this bifunctional molecule induces the formation of a ternary complex between the target protein, the PROTAC, and the CRBN E3 ubiquitin ligase. Recruitment of CRBN leads to ubiquitination of the target protein, marking it for proteasomal degradation. The PEG1 linker introduces flexibility and hydrophilicity, potentially improving the pharmacokinetic and physicochemical properties of the resulting PROTAC.

Applications

This E3 ligase ligand-linker conjugate is widely used in the discovery and development of PROTAC molecules. (S,R,S)-AHPC-PEG1-NH2 hydrochloride enables researchers to efficiently synthesize novel PROTACs for targeted protein degradation studies, mechanism-of-action investigations, and drug discovery programs across oncology, neurodegenerative diseases, and immunology. Its modular design streamlines structure-activity relationship (SAR) studies and accelerates the optimization of PROTAC efficacy, selectivity, and drug-like properties.

The E3 Ligase Ligand-Linker Conjugate, (S,R,S)-AHPC-PEG1-NH2 hydrochloride, plays a pivotal role in PROTACs by facilitating targeted protein degradation. This molecule offers flexibility and efficiency in linking ligands to target proteins, enhancing the selectivity and potency of the degradation process. The following provides a detailed description of this molecule's linker, ligand, and reactive site.

Linker: The linker in this molecule is a PEG1 unit, which offers moderate flexibility and hydrophilicity, enhancing solubility and bioavailability. Its short length allows for efficient spatial orientation between the ligand and the target protein, while its non-cleavable nature ensures stability during the degradation process.

Ligand: The ligand component, AHPC, is a small molecule designed to bind specifically to the E3 ligase CRBN. Its stereochemically defined structure ensures high affinity and selectivity, facilitating the recruitment of the E3 ligase to the target protein, thus promoting ubiquitination and subsequent degradation.

Reactive Site: The reactive site in this conjugate is the terminal amine group of the PEG1 linker, which enables coupling with the target protein ligand through amide bond formation. Recommended reaction types include EDC/NHS-mediated coupling or click chemistry for efficient conjugation.

Recommended Target Protein Ligand: The ideal warhead for this molecule is a small molecule inhibitor or substrate mimic that can selectively bind the target protein. This ensures precise targeting and degradation, making it suitable for applications in studying protein function and validating therapeutic targets in cellular models.