Thalidomide-O-amido-PEG2-C2-NH2 (TFA)

Background Introduction

Thalidomide-O-amido-PEG2-C2-NH2 (TFA) is a specialized E3 ligase ligand-linker conjugate designed for use in PROTAC (Proteolysis Targeting Chimera) technology. As a thalidomide derivative, it effectively recruits the cereblon E3 ubiquitin ligase complex. The addition of a PEG2-C2-amido linker and an amine (NH2) functional group facilitates flexible and straightforward coupling with various target ligands, making it an ideal building block for custom PROTAC synthesis.

Mechanism

Thalidomide-O-amido-PEG2-C2-NH2 (TFA) works by leveraging the thalidomide moiety to bind to the cereblon (CRBN) E3 ubiquitin ligase. The conjugate’s PEG2-C2-amido linker provides optimal spatial orientation and solubility, connecting the E3 ligase ligand to another small molecule ligand that targets a specific protein of interest. This bifunctional PROTAC molecule brings the E3 ligase and the target protein into close proximity, promoting ubiquitination and subsequent proteasomal degradation of the target protein. This mechanism offers potent, selective protein knockdown with advantages over traditional inhibition techniques.

Applications

Thalidomide-O-amido-PEG2-C2-NH2 (TFA) is widely used in the design and synthesis of custom PROTACs for targeted protein degradation research. It serves as an essential intermediate for conjugating cereblon-binding ligands to target protein ligands in innovative drug development, including cancer, neurodegenerative, and autoimmune disease models. Researchers use this conjugate to streamline PROTAC development workflows, enabling rapid evaluation of new protein targets, precise mechanism-of-action studies, and high-throughput screening campaigns for next-generation therapeutics.