Thalidomide-O-PEG4-C2-acid

Background Introduction

Thalidomide-O-PEG4-C2-acid is a specialized E3 ligase ligand-linker conjugate designed for advanced drug discovery applications, particularly in the development of PROTACs (Proteolysis Targeting Chimeras). Incorporating the thalidomide-based cereblon (CRBN) ligand, a PEG4 spacer, and a carboxylic acid functional group, this molecule serves as a versatile intermediate for constructing targeted protein degraders.

Mechanism

The mechanism of Thalidomide-O-PEG4-C2-acid centers on its role as an E3 ligase recruiter within bifunctional molecules like PROTACs. The thalidomide moiety selectively binds to cereblon, an E3 ubiquitin ligase substrate receptor, facilitating the recruitment of the ubiquitin-proteasome system. The PEG4 linker provides optimal spatial orientation and flexibility, while the C2-acid allows for efficient conjugation with a wide variety of target protein ligands. When incorporated into a PROTAC, Thalidomide-O-PEG4-C2-acid enables proximity-induced ubiquitination and subsequent proteasomal degradation of the target protein.

Applications

Thalidomide-O-PEG4-C2-acid is widely used in the design and synthesis of cereblon-based PROTACs for targeted protein degradation. Its applications include the development of chemical tools for elucidating protein function, validation of new therapeutic targets, and pioneering new treatment strategies in oncology, neurodegeneration, and other disease areas. This conjugate is valued for its compatibility in medicinal chemistry workflows, allowing for efficient assembly of multifunctional degraders that exploit the ubiquitin-proteasome pathway.

• Polyethylene glycol (PEG4) linker improves solubility and pharmacokinetic properties in PROTAC design.
• Carboxylic acid functional group allows flexible conjugation with diverse warheads and bioactive molecules.