Pomalidomide-PEG6-Alkyne

Background Introduction

Pomalidomide-PEG6-Alkyne is a bifunctional chemical reagent designed for targeted protein degradation research. This molecule combines pomalidomide, a well-known cereblon (CRBN) E3 ligase ligand, with a six-unit polyethylene glycol (PEG6) linker terminated with an alkyne functional group. The modular structure of Pomalidomide-PEG6-Alkyne makes it an essential building block for constructing PROTACs (Proteolysis Targeting Chimeras) and other heterobifunctional molecules, widely used in the development of next-generation therapeutic agents.

Mechanism

Pomalidomide-PEG6-Alkyne achieves its function by leveraging the specific binding of pomalidomide to CRBN, a substrate receptor of the CRL4 E3 ubiquitin ligase complex. The PEG6 linker provides optimal spatial separation and flexibility, while the alkyne moiety allows for facile click chemistry-based conjugation with a variety of targeting ligands, such as small molecules or peptides. In the context of PROTAC design, the resulting conjugate recruits a protein of interest into proximity with the E3 ligase, promoting the ubiquitination and subsequent proteasomal degradation of the target protein.

Applications

Pomalidomide-PEG6-Alkyne is primarily applied in the synthesis of PROTAC molecules via copper-catalyzed azide-alkyne cycloaddition (CuAAC) click chemistry. Its use enables researchers to systematically explore targeted protein degradation as a therapeutic strategy for previously 'undruggable' proteins. Typical applications include chemical biology studies, mechanistic investigations of E3 ligase function, generation of custom PROTAC libraries, and drug discovery programs focused on cancer, neurodegenerative diseases, and immune disorders.

• PEG6-based linker provides superior water solubility and flexible spacer length for optimal PROTAC design.
• Terminal alkyne group enables efficient and selective click chemistry conjugation for versatile PROTAC assembly.