Pomalidomide-PEG6-CO2H

Background Introduction

Pomalidomide-PEG6-CO2H is a specialized bifunctional molecule designed for targeted protein degradation applications. This conjugate consists of pomalidomide, a well-characterized cereblon (CRBN) E3 ligase ligand, linked to a carboxylic acid-terminated hexamethylene glycol (PEG6) spacer. The extended PEG6 linker enhances solubility and spatial flexibility, enabling efficient coupling of target-binding ligands for the construction of PROTACs (Proteolysis Targeting Chimeras).

Mechanism

The mechanism of action for Pomalidomide-PEG6-CO2H revolves around harnessing the ubiquitin-proteasome system for targeted protein degradation. Pomalidomide binds selectively to the cereblon E3 ubiquitin ligase within the cell. The PEG6 linker provides an optimal distance and flexibility for the attachment of various protein-targeting ligands via its terminal carboxylic acid group. In PROTAC design, once conjugated to a ligand for a protein of interest (POI), Pomalidomide-PEG6-CO2H simultaneously recruits both the CRBN E3 ligase and the POI, inducing their proximity. This ternary complex formation triggers ubiquitination of the POI by the ligase, marking it for degradation by the cellular proteasome.

Applications

Pomalidomide-PEG6-CO2H is widely utilized in the development of CRBN-based PROTACs and related bifunctional molecules for targeted protein degradation studies. Its applications include: (1) constructing customized PROTACs by linking to various protein-specific ligands through the PEG6-carboxyl group; (2) facilitating the study of structure-activity relationships and linker optimization in PROTAC research; (3) advancing drug discovery pipelines by enabling selective removal of disease-relevant proteins in oncology, neurodegenerative diseases, and immunological disorders. The PEG6 linker imparts improved pharmacokinetics and cell permeability, making it an ideal component for chemical biology, medicinal chemistry, and preclinical therapeutic research.

• PEG6 linker increases solubility and improves pharmacokinetic properties of PROTAC molecules.
• Carboxylic acid (CO2H) terminal enables versatile conjugation with target warheads for efficient CRBN E3 ligase recruitment.