Pomalidomide-PEG3-Alkyne

Background Introduction

Pomalidomide-PEG3-Alkyne is a versatile E3 ligase ligand-linker conjugate, featuring pomalidomide—a cereblon (CRBN) binding ligand—connected via a triethylene glycol (PEG3) spacer to an alkyne functional group. This chemically defined, modular structure enables its widespread use in targeted protein degradation research, particularly in the development of PROTAC (Proteolysis Targeting Chimera) molecules and related bifunctional degraders.

Mechanism

The mechanism of Pomalidomide-PEG3-Alkyne involves its ability to recruit the E3 ubiquitin ligase cereblon (CRBN) through the pomalidomide moiety. The PEG3 linker imparts optimal spatial flexibility and solubility, while the terminal alkyne group enables efficient 'click' chemistry (e.g., copper-catalyzed azide-alkyne cycloaddition, CuAAC) for conjugation to diverse ligands or small molecules. Once incorporated into a PROTAC, the molecule brings a target protein into proximity with the CRBN E3 ligase, facilitating its ubiquitination and subsequent degradation by the proteasome.

Applications

Pomalidomide-PEG3-Alkyne is widely applied in chemical biology and drug discovery for the synthesis of PROTACs targeting a diverse range of proteins. The terminal alkyne allows facile attachment to protein-binding ligands via click chemistry, enabling the rapid generation of customized bifunctional degraders. Additionally, this conjugate serves as a key intermediate for the development of molecular glues, targeted protein degradation probes, and chemical proteomics tools. It supports research in oncology, neurodegenerative diseases, and other therapeutic areas where controlled protein knockdown is desired.