Thalidomide-PEG4-NH2 hydrochloride

Background Introduction

Thalidomide-PEG4-NH2 hydrochloride is a specialized E3 Ligase Ligand-Linker Conjugate designed for use in targeted protein degradation technologies such as PROTACs (Proteolysis Targeting Chimeras). This conjugate combines the cereblon (CRBN) binding ligand, thalidomide, with a hydrophilic polyethylene glycol (PEG4) linker ending in an amine functional group, facilitating customized conjugation. Its salt form improves solubility and handling for research and development purposes.

Mechanism

The mechanism of Thalidomide-PEG4-NH2 hydrochloride is centered around harnessing the power of the ubiquitin-proteasome system for specific protein degradation. Thalidomide acts as an E3 ligase ligand, recruiting the CRBN component of the CRL4 E3 ubiquitin ligase complex. When the PEG4-NH2 linker is covalently attached to a ligand targeting a protein of interest, the resulting PROTAC molecule brings the target protein in proximity to the E3 ligase. This close association induces ubiquitination and subsequent proteasomal degradation of the target protein in cells, representing a targeted and reversible alternative to gene editing.

Applications

Thalidomide-PEG4-NH2 hydrochloride is widely used in the development of PROTACs and molecular glue degraders. Its modular design enables researchers to construct customized bifunctional molecules to degrade pathogenic proteins implicated in cancer, neurodegenerative diseases, and other conditions. Additionally, its application extends to the study of E3 ligase biology, optimization of linker composition in protein degradation technology, and the synthesis of tool compounds for mechanism-of-action studies and drug target validation.

• Flexible PEG4 linker improves solubility and cellular permeability for efficient PROTAC design.
• Amine-terminated structure facilitates rapid conjugation with diverse warheads for targeted protein degradation.