Thalidomide-O-C4-COOH

Background Introduction

Thalidomide-O-C4-COOH is a specialized E3 ligase ligand-linker conjugate derived from thalidomide, a well-characterized immunomodulatory drug. This compound features a thalidomide moiety linked through a four-carbon (C4) linker terminating in a carboxylic acid (COOH) functional group. Thalidomide-based ligands have become essential in the development of targeted protein degradation technologies, such as PROTACs (Proteolysis Targeting Chimeras), due to their high affinity for the cereblon (CRBN) E3 ubiquitin ligase.

Mechanism

Thalidomide-O-C4-COOH exploits the natural binding affinity of thalidomide derivatives to the CRBN E3 ubiquitin ligase. In PROTAC strategies, this ligand-linker construct is covalently attached to a target-protein binder, forming a bifunctional molecule. The thalidomide moiety recruits the CRBN E3 ligase, while the other end binds the protein-of-interest. This brings the target protein into proximity with the cellular ubiquitination machinery, leading to its ubiquitination and selective proteasomal degradation. The four-carbon linker and carboxyl functional group provide synthetic versatility for conjugation to various target ligands, thereby facilitating the generation of diverse PROTAC molecules.

Applications

Thalidomide-O-C4-COOH is extensively used in the chemical synthesis of next-generation PROTACs and related targeted protein degradation modalities. Researchers utilize this conjugate as an E3 ligase-recruiting building block to create cell-permeable PROTACs that selectively eliminate disease-relevant proteins, including oncogenic, epigenetic, and neurodegenerative targets. Its design makes it ideal for structure-activity relationship (SAR) studies, discovery of novel therapeutics, and proof-of-concept experiments in both academic and pharmaceutical research settings focused on drug discovery and chemical biology.