Thalidomide-PEG4-Propargyl

Background Introduction

Thalidomide-PEG4-Propargyl is a sophisticated E3 ligase ligand-linker conjugate designed for use in targeted protein degradation strategies, particularly in the development of proteolysis targeting chimeras (PROTACs). By leveraging the binding affinity of thalidomide for the cereblon (CRBN) E3 ligase, this compound is widely employed in chemical biology and drug discovery to harness the cellular ubiquitin-proteasome system for selective protein knockdown.

Mechanism

The mechanism of Thalidomide-PEG4-Propargyl involves its thalidomide moiety, which selectively binds to the CRBN E3 ubiquitin ligase complex. The PEG4 linker provides optimal spatial flexibility, facilitating the attachment of this conjugate to a target ligand through the propargyl functional group via click chemistry. In a PROTAC construct, this design enables the simultaneous recruitment of CRBN to the target protein, triggering ubiquitination and subsequent proteasomal degradation of the target protein inside cells.

Applications

Thalidomide-PEG4-Propargyl is extensively utilized in the synthesis of PROTAC molecules for research and drug discovery. It enables the creation of bifunctional molecules to degrade disease-related proteins, aiding in cancer, neurodegeneration, and immunomodulation studies. Its propargyl group supports rapid and efficient target linkage through bioorthogonal click chemistry, streamlining the development of next-generation therapeutic agents and chemical biology probes focused on induced protein degradation.