Thalidomide-O-amido-PEG2-C2-NH2 hydrochloride

Background Introduction

Thalidomide-O-amido-PEG2-C2-NH2 hydrochloride is a specialized small-molecule reagent combining a thalidomide-based E3 ligase ligand with a polyethylene glycol (PEG2) linker and a terminal amine moiety. This conjugate is designed to facilitate the development and optimization of Proteolysis Targeting Chimeras (PROTACs), enabling targeted protein degradation by harnessing the cellular ubiquitin-proteasome system. Its structural features make it a valuable tool for drug discovery and research into targeted protein regulation.

Mechanism

This compound works as an E3 ligase ligand-linker conjugate. The thalidomide moiety selectively recruits the cereblon (CRBN) E3 ubiquitin ligase complex, an essential component for tagging target proteins for degradation. The PEG2-C2 linker offers an optimal spatial arrangement for connecting the E3 ligase ligand to a target protein ligand. The terminal NH2 group allows for versatile chemical conjugation, enabling the synthesis of bifunctional PROTAC molecules. Once the PROTAC is formed, it bridges the target protein and the E3 ligase, promoting polyubiquitination and subsequent proteasomal degradation of the target.

Applications

Thalidomide-O-amido-PEG2-C2-NH2 hydrochloride is widely employed in the design and synthesis of PROTACs for selective protein degradation. It serves as a modular intermediate for generating a variety of PROTACs by coupling with different ligands for target proteins, facilitating research in oncology, neurodegenerative diseases, and immunology. Additionally, it aids in structure-activity relationship (SAR) studies, linker optimization, and the creation of chemical biology probes. Its utility supports both academic and pharmaceutical research teams aiming to explore novel therapeutic modalities and target validation platforms.

• Amine-terminated PEG linker offers superior solubility and flexible conjugation options for custom PROTAC development.
• Optimized CRBN ligand ensures high binding affinity, enhancing selective protein degradation in targeted therapies.

ConcentrationVolumeMass	1 mg	5 mg	10 mg
0.5 mM	4.01 mL	20.04 mL	40.09 mL
2.5 mM	0.8 mL	4.01 mL	8.02 mL
5 mM	0.4 mL	2 mL	4.01 mL
25 mM	0.08 mL	0.4 mL	0.8 mL

Thalidomide-O-amido-PEG2-C2-NH2 hydrochloride serves as a versatile E3 Ligase Ligand-Linker Conjugate, crucial in the design of PROTACs for targeted protein degradation. This compound effectively bridges the E3 ligase and target protein, enhancing specificity and efficacy in protein degradation research. The following provides a detailed description of this molecule's linker, ligand, and reactive site.

Linker: The linker in this molecule is a PEG2-C2 chain, offering moderate flexibility and an optimal length for spatial positioning. This linker is non-cleavable, ensuring stability and sustained interaction between the E3 ligase and the target protein, crucial for efficient degradation.

Ligand: The ligand component is derived from thalidomide, a well-characterized small molecule that binds to the cereblon E3 ligase. Its structural characteristics include a glutarimide moiety, which facilitates high-affinity binding, thus enhancing the recruitment of the E3 ligase to the target protein.

Reactive Site: The reactive site features an amido group that couples with the target protein ligand through amide bond formation. Recommended reaction types include amidation or peptide coupling, which are robust and reliable for forming stable linkages in diverse experimental settings.

Recommended Target Protein Ligand: The ideal warhead for this conjugate is a small molecule with a nucleophilic group, such as an amine or hydroxyl, compatible with the amido group. This compatibility allows for efficient conjugation, enhancing the degradation of target proteins. Applications include the study of protein-protein interactions and the validation of novel therapeutic targets in cellular systems.