Pomalidomide-PEG6-butyl iodide

Background Introduction

Pomalidomide-PEG6-butyl iodide is a specialized E3 ligase ligand-linker conjugate designed for targeted protein degradation technologies, such as PROTACs. This compound features pomalidomide, a small molecule known for its ability to recruit the cereblon (CRBN) E3 ubiquitin ligase. The PEG6 linker and butyl iodide moiety provide a flexible, functionalizable scaffold for conjugation to warhead molecules that bind target proteins, enabling efficient development of novel PROTAC degraders.

Mechanism

Pomalidomide-PEG6-butyl iodide operates by utilizing the pomalidomide moiety to bind the CRBN E3 ligase. The PEG6 (polyethylene glycol) linker imparts water solubility and spatial flexibility, while the terminal butyl iodide function serves as a handle for chemical modification or attachment to a target-binding ligand (warhead). In the context of a PROTAC molecule, this conjugate links the CRBN E3 ligase to a specific target protein, facilitating the formation of a ternary complex. The proximity induced by this complex results in ubiquitination and subsequent proteasomal degradation of the target protein.

Applications

Pomalidomide-PEG6-butyl iodide is widely used in the design and synthesis of PROTACs and related targeted protein degradation tools. Researchers use this conjugate to construct bifunctional molecules that degrade disease-relevant proteins, making it valuable for drug discovery, validation of therapeutic targets, and development of chemical probes. It is especially relevant in oncology, neurodegenerative disorders, and immunology research, where selective protein degradation offers advantages over traditional inhibition. Additionally, the compound accelerates the assembly of custom PROTAC libraries by providing a ready-to-use CRBN ligand-linker scaffold for rapid SAR (structure-activity relationship) studies.

• Hydrophilic PEG6 linker improves solubility and pharmacokinetic properties of PROTAC molecules.
• Iodide functional group enables site-specific conjugation for efficient CRBN E3 ligase recruitment in PROTAC design.