Thalidomide-O-amido-C4-NH2

Background Introduction

Thalidomide-O-amido-C4-NH2 is a versatile E3 ligase ligand-linker conjugate, widely employed in PROTAC (Proteolysis Targeting Chimera) technology. This compound incorporates a thalidomide-based ligand, known for its high affinity to the cereblon (CRBN) E3 ubiquitin ligase protein, with an amide-functionalized linker. The C4 chain and terminal amine (NH2) groups provide flexibility and compatibility for conjugation to various target protein ligands, facilitating the design of next-generation protein degraders.

Mechanism

Thalidomide-O-amido-C4-NH2 operates by recruiting the CRBN E3 ligase component of the ubiquitin-proteasome system. The thalidomide moiety selectively binds to CRBN, while the amido-C4-NH2 linker serves as a modular handle for attaching different target protein ligands. In PROTAC development, this conjugate acts as the E3 ligase 'arm,' enabling bifunctional molecules to induce proximity between CRBN and the target protein. This proximity triggers ubiquitination of the target protein, leading to its subsequent recognition and degradation by the cellular proteasome machinery.

Applications

Thalidomide-O-amido-C4-NH2 is primarily used in the synthesis of CRBN-based PROTACs for targeted protein degradation studies. Its amino-terminated linker allows efficient conjugation with custom ligands to degrade a wide spectrum of disease-relevant proteins. Common applications include: drug discovery, exploring mechanisms of protein homeostasis, validating novel therapeutic targets, and the development of tools for chemical biology research. As part of the PROTAC toolkit, Thalidomide-O-amido-C4-NH2 enables the rapid assembly of protein degraders to accelerate lead optimization and preclinical research in oncology, neuroscience, and beyond.