Thalidomide-O-C2-acid

Background Introduction

Thalidomide-O-C2-acid is a versatile E3 ligase ligand-linker conjugate specially engineered for use in PROTAC (Proteolysis Targeting Chimera) technology and related targeted protein degradation strategies. This derivative of thalidomide features an O-linked ethylene-glycol-based acid (C2 acid) modification, providing a convenient reactive handle for further conjugation, making it an ideal intermediate for custom PROTAC synthesis. Thalidomide derivatives are widely used as cereblon (CRBN) E3 ligase ligands, facilitating targeted protein degradation applications in drug discovery and biomedical research.

Mechanism

The mechanism of Thalidomide-O-C2-acid in PROTAC design involves its role as an E3 ligase ligand. By covalently attaching this compound to a target protein ligand via the carboxylic acid linker, researchers create bifunctional molecules (PROTACs) that simultaneously recruit the CRBN E3 ligase and bring it into proximity with a target protein. This induced proximity leads to ubiquitination of the target protein by the E3 ligase complex, subsequently triggering proteasomal degradation. The C2 acid linker enables flexible and efficient conjugation to various chemical scaffolds, thereby expanding the range of protein targets and PROTAC architectures.

Applications

Thalidomide-O-C2-acid is primarily used in the synthesis of PROTAC molecules for targeted protein degradation. Its applications span small-molecule drug discovery, especially in oncology and neurodegeneration research, where selective protein knockdown is needed. Researchers employ this intermediate to create novel PROTACs that harness the cereblon E3 ligase system for in vitro and in vivo studies, mechanism-of-action investigations, and the validation of new protein targets. The product is also valuable in the development of molecular glues, chemical biology platforms, and next-generation therapeutics exploiting the ubiquitin-proteasome pathway.

• Carboxylic acid functional group enables reliable coupling to a variety of warheads or linkers for flexible PROTAC design.
• Ideal for CRBN E3 ligase recruitment, facilitating targeted protein degradation applications.