Pomalidomide-PEG4-C2-NH2 hydrochloride

Background Introduction

Pomalidomide-PEG4-C2-NH2 hydrochloride is a specialized E3 ligase ligand-linker conjugate designed for targeted protein degradation applications. This compound integrates pomalidomide, a well-established ligand for the cereblon (CRBN) E3 ubiquitin ligase, with a hexadecaethylene glycol-based PEG4 spacer and an amine-terminated linker, enabling versatile attachment to various molecular warheads or cargos used in PROTAC (Proteolysis Targeting Chimera) design.

Mechanism

The mechanism of action of Pomalidomide-PEG4-C2-NH2 hydrochloride centers on its ability to recruit the CRBN E3 ubiquitin ligase when incorporated into bifunctional PROTACs. The pomalidomide moiety selectively binds to CRBN, facilitating the proximity-induced ubiquitination of the protein of interest (POI) that is tethered via the linker. The attached linker (PEG4-C2-NH2) offers optimal flexibility and solubility, reducing steric hindrance and improving the pharmacokinetic properties of the resulting conjugate. This design enables efficient polyubiquitination and subsequent proteasomal degradation of the POI, allowing for selective post-translational protein knockdown.

Applications

Pomalidomide-PEG4-C2-NH2 hydrochloride is widely used in chemical biology and drug discovery for the development of novel PROTACs and molecular glues targeting the CRBN E3 ligase. Its application includes building custom PROTAC molecules for targeted degradation of disease-relevant proteins, enabling research in oncology, neurodegenerative disorders, and immunology. Researchers also employ this conjugate in screening platforms for validating E3 ligase engagement and optimizing linker lengths for structure-activity relationship (SAR) studies. The hydrochloride salt form enhances its stability and ease of use in medicinal chemistry workflows, supporting both in vitro and in vivo studies.

• PEG4-based flexible linker improves solubility and pharmacokinetic properties of resulting PROTACs.
• Tailored for efficient CRBN E3 ligase recruitment, enabling potent targeted protein degradation applications.