Pomalidomide-PEG2-NH2 hydrochloride

Background Introduction

Pomalidomide-PEG2-NH2 hydrochloride is an advanced bifunctional E3 ligase ligand-linker conjugate designed for the development of next-generation PROTACs (Proteolysis Targeting Chimeras). Pomalidomide, a clinically validated immunomodulatory agent commonly used as an E3 ligase binder, is conjugated through a hydrophilic PEG2 linker with a terminal amine. This enables versatile chemical modifications and improved pharmacokinetic properties for targeted protein degradation applications.

Mechanism

This conjugate functions by recruiting the cereblon (CRBN) E3 ubiquitin ligase when incorporated into a PROTAC molecule. The pomalidomide moiety binds specifically to the CRBN E3 ligase, while the PEG2 linker provides optimal spatial orientation, solubility, and reduced steric hindrance. The terminal NH2 group serves as a reactive handle, facilitating covalent attachment to protein-of-interest (POI) ligands or other molecular modules. Once assembled into a PROTAC, the conjugate brings the target protein and E3 ligase into close proximity, promoting ubiquitination and subsequent proteasomal degradation of the POI.

Applications

Pomalidomide-PEG2-NH2 hydrochloride is widely used in PROTAC research for the synthesis of novel PROTACs aimed at targeted protein degradation. Its applications span academic and pharmaceutical settings, including the development of chemical probes, investigation of disease pathways, and drug discovery targeting oncology, neurodegenerative diseases, and other therapeutic areas where selective protein knockdown is desired. The PEG2 linker offers enhanced solubility and cell permeability, making this conjugate ideal for generating PROTACs with improved in vivo efficacy and pharmacokinetics.