Thalidomide-O-amido-PEG-C2-NH2

Background Introduction

Thalidomide-O-amido-PEG-C2-NH2 is a specialized E3 ligase ligand-linker conjugate designed for use in the development of PROTACs (Proteolysis Targeting Chimeras). The molecule features a thalidomide-based ligand, known to bind cereblon (CRBN) E3 ubiquitin ligase, and is functionalized with a polyethylene glycol (PEG) linker and a terminal amine group (NH2). E3 ligase ligand-linker conjugates like this one are crucial building blocks for researchers working in targeted protein degradation and drug discovery.

Mechanism

Thalidomide-O-amido-PEG-C2-NH2 operates by harnessing the power of the ubiquitin-proteasome system. The thalidomide moiety selectively binds to the CRBN E3 ligase component, recruiting it to the target protein when included in a PROTAC design. The PEG linker provides optimal spatial configuration, while the terminal amine allows for convenient conjugation to a target-binding ligand. When incorporated into a bifunctional PROTAC molecule, this conjugate facilitates the proximity-induced ubiquitination of the target protein, ultimately leading to its recognition and degradation by the proteasome.

Applications

Thalidomide-O-amido-PEG-C2-NH2 is widely used in PROTAC research and targeted protein degradation studies. Its well-characterized CRBN-binding motif makes it ideal for conjugation with various target ligands, enabling the design of custom PROTACs against a wide spectrum of disease-associated proteins. Key applications include: functional validation of potential drug targets, development of next-generation therapeutics for cancer and neurodegenerative diseases, and creation of research tools to study the ubiquitin-proteasome pathway. Additionally, its PEGylated linker enhances cellular permeability and solubility, broadening its utility in medicinal chemistry and chemical biology.