Pomalidomide-PEG3-azide

Background Introduction

Pomalidomide-PEG3-azide is a versatile molecular tool used in the development of targeted protein degradation technologies such as PROTACs (Proteolysis Targeting Chimeras). By combining the immunomodulatory drug pomalidomide, a polyethylene glycol (PEG3) spacer, and an azide functional group, this ligand-linker conjugate enables the creation of bifunctional molecules designed to recruit E3 ubiquitin ligases to target proteins. Its modular structure is ideal for click chemistry, allowing for rapid and efficient synthesis of novel PROTAC molecules.

Mechanism

Pomalidomide-PEG3-azide operates by leveraging pomalidomide's ability to recruit the CRBN (cereblon) E3 ubiquitin ligase complex. The PEG3 linker provides optimal spatial separation, enhancing molecular flexibility and bioavailability. The terminal azide group allows for copper-catalyzed azide-alkyne cycloaddition ('click chemistry') to attach various protein-targeting moieties. Once the resulting PROTAC binds to both the target protein and the CRBN E3 ligase, it facilitates protein ubiquitination and subsequent proteasomal degradation, effectively reducing the cellular levels of the target protein.

Applications

Pomalidomide-PEG3-azide is widely used in PROTAC research and drug discovery. Its main application is in the synthesis of PROTACs aimed at targeted protein degradation, particularly for disease-relevant targets that are otherwise considered 'undruggable.' Researchers use this conjugate to design and optimize PROTAC libraries, enabling rapid prototyping of new molecules. It is also valuable in studies exploring structure-activity relationships (SAR), E3 ligase engagement, and the development of next-generation therapeutics for cancer, neurodegenerative diseases, and autoimmune conditions.

• Azide terminal group enables versatile click chemistry for efficient conjugation with diverse payloads or targeting ligands.
• PEG3 linker provides increased solubility and flexibility, optimizing performance in CRBN-recruiting PROTAC applications.