Thalidomide-O-C6-COOH

Background Introduction

Thalidomide-O-C6-COOH is a specialized E3 ligase ligand-linker conjugate used primarily in the development of PROTACs (Proteolysis Targeting Chimeras). This compound consists of a thalidomide derivative, a clinically validated E3 ligase ligand, attached to a 6-carbon linker featuring a terminal carboxylic acid group. This structural design enables straightforward conjugation to various target protein ligands, making it a versatile tool in chemical biology and drug discovery.

Mechanism

Thalidomide-O-C6-COOH operates by leveraging the selective binding of thalidomide to the CRBN (cereblon) E3 ubiquitin ligase. The thalidomide moiety recruits CRBN, while the C6 linker and carboxylic acid handle facilitate covalent attachment to ligands targeting specific proteins of interest. Once conjugated, the resulting PROTAC molecule brings the target protein into proximity with CRBN E3 ligase, leading to ubiquitination and subsequent proteasomal degradation of the target protein. This targeted protein degradation mechanism enables selective and efficient removal of disease-related proteins within cells.

Applications

Thalidomide-O-C6-COOH is widely used for the synthesis of CRBN-based PROTACs in both academic research and pharmaceutical development. Its applications include the construction of bifunctional degraders for target validation, studying protein function via degradation, and discovering novel therapeutics for cancer, neurodegenerative diseases, and autoimmune disorders. Moreover, the terminal carboxylic acid group allows flexible conjugation chemistry, enabling medicinal chemists to rapidly generate PROTAC libraries for high-throughput screening and structure-activity relationship (SAR) studies.