Thalidomide-O-amido-C4-NH2 (TFA)

Background Introduction

Thalidomide-O-amido-C4-NH2 (TFA) is a versatile E3 ligase ligand-linker conjugate commonly used in the design and development of proteolysis targeting chimeras (PROTACs). Thalidomide derivatives have emerged as an essential tool in targeted protein degradation platforms due to their ability to recruit the CRBN (Cereblon) E3 ubiquitin ligase. The incorporation of a suitable linker, such as the four-carbon (C4) amido linker in this product, allows seamless conjugation with a wide range of protein-of-interest ligands, enabling the targeted degradation of disease-relevant proteins that are often considered 'undruggable.'

Mechanism

Thalidomide-O-amido-C4-NH2 (TFA) functions as one half of a bifunctional PROTAC molecule. The thalidomide moiety selectively binds to the CRBN component of the E3 ubiquitin ligase complex. The C4-amido linker provides optimal spacing and chemical flexibility for conjugation with a ligand that binds the target protein. Once the two ligands are coupled and the resulting PROTAC is introduced into cells, it brings the target protein into proximity with the CRBN E3 ligase, facilitating ubiquitination of the target and subsequent proteasomal degradation. This mode of action enables selective and efficient removal of pathogenic proteins from cells.

Applications

Thalidomide-O-amido-C4-NH2 (TFA) is widely utilized in medicinal chemistry and chemical biology for PROTAC design and synthesis. Key applications include: (1) constructing bespoke PROTACs for target validation or drug discovery research, (2) enabling targeted degradation of oncogenic, epigenetic, or misfolded proteins implicated in cancer, neurodegenerative disorders, and other diseases, and (3) facilitating high-throughput screening campaigns aimed at identifying novel protein degraders. This E3 ligase ligand-linker conjugate is an essential building block for researchers developing next-generation therapeutics using targeted protein degradation technology.