Thalidomide-O-amido-PEG1-(C1-​PEG)2-C2-NH2

Background Introduction

Thalidomide-O-amido-PEG1-(C1-PEG)2-C2-NH2 is an E3 Ligase Ligand-Linker Conjugate designed for advanced applications in targeted protein degradation. With thalidomide as the active ligand moiety, this innovative compound exploits the well-characterized cereblon (CRBN) E3 ligase for the recruitment necessary in PROTAC (Proteolysis Targeting Chimera) technology. The inclusion of a flexible PEG-based linker provides optimal spatial orientation and enhances water solubility, making it suitable for efficient and selective target engagement in PROTAC development.

Mechanism

This molecule features a thalidomide-derived E3 ligase ligand tethered via a PEGylated linker to a reactive amine. The thalidomide segment specifically binds to the CRBN E3 ubiquitin ligase, serving as an anchor in the ternary complex formation essential for PROTAC-induced degradation. The PEG linker imparts flexibility, hydrophilicity, and reduces steric hindrance, thereby facilitating efficient proximity-induced ubiquitination when conjugated to a target protein ligand via its terminal amine. Such design enhances the overall bioavailability, target accessibility, and pharmacokinetic properties of custom PROTACs.

Applications

Thalidomide-O-amido-PEG1-(C1-PEG)2-C2-NH2 is a versatile tool in the design and synthesis of PROTACs for chemical biology research and drug discovery. Its key applications include: (1) Synthesis of CRBN-based PROTAC molecules for targeted protein degradation studies; (2) Investigation of protein function via selective degradation in cellular and in vivo models; (3) Development of next-generation therapeutics for cancer, neurodegenerative, and immunological diseases; and (4) Exploration of linker length effects in SAR (structure-activity relationship) studies of bifunctional degrader compounds. This conjugate offers researchers a reliable starting point for modular assembly and optimization of custom degraders.