Thalidomide-5-O-CH2-COOH

Background Introduction

Thalidomide-5-O-CH2-COOH is a chemically modified derivative of thalidomide, designed specifically as a functional E3 ligase ligand-linker conjugate. This molecule strategically incorporates a carboxylic acid group into thalidomide’s 5-position via a methylene spacer, facilitating efficient conjugation to additional components for targeted protein degradation applications. E3 ligase ligands play a pivotal role in the development of PROTACs (Proteolysis Targeting Chimeras), enabling the selective degradation of disease-relevant proteins.

Mechanism

The primary mechanism of Thalidomide-5-O-CH2-COOH involves its function as a cereblon (CRBN) E3 ubiquitin ligase recruiting element. When incorporated into PROTACs, the thalidomide-based ligand binds CRBN, forming part of an induced ternary complex with the target protein and E3 ligase. The carboxylic acid linker allows chemical attachment to a targeting ligand via amide or ester bond formation, effectively bringing the E3 ligase and the protein of interest into close spatial proximity. This proximity promotes ubiquitination and subsequent proteasomal degradation of the target protein, resulting in precise and efficient protein knockdown.

Applications

Thalidomide-5-O-CH2-COOH is widely utilized as a modular building block in the synthesis of PROTAC molecules, molecular glues, and other targeted protein degradation compounds. Its enhanced reactivity and optimal linker position make it ideal for conjugation with a variety of ligands targeting oncology, neurology, or immunology-relevant proteins. Researchers employ this conjugate in preclinical studies for the rational design of next-generation therapeutics, high-throughput screening of degrader libraries, and expanding the coverage of druggable proteomes. Thus, it serves as a key reagent in both academic and industrial research aimed at developing novel small molecule degraders.

• Carboxyl-functionalized thalidomide derivative allows for versatile conjugation in PROTAC assembly.
• Specifically tailored for efficient recruitment of CRBN E3 ligase in targeted protein degradation applications.