Pomalidomide-PEG1-C2-N3

Background Introduction

Pomalidomide-PEG1-C2-N3 is a specialized E3 ligase ligand-linker conjugate designed for use in targeted protein degradation applications, such as the development of PROTACs (Proteolysis Targeting Chimeras). This compound leverages the well-established cereblon (CRBN)-recruiting capabilities of pomalidomide, combined with a versatile PEG-based linker and a terminal azide (N3) functional group. This modular structure makes it an ideal chemical building block for researchers developing next-generation protein degradation tools.

Mechanism

Pomalidomide acts as an E3 ligase ligand, specifically binding to the cereblon (CRBN) component of the E3 ubiquitin ligase complex. The PEG1-C2 linker enhances solubility and provides spatial flexibility, facilitating optimal ternary complex formation in PROTAC designs. The terminal azide (N3) serves as a bioorthogonal reactive handle, enabling efficient click chemistry conjugation to various targeting ligands. When incorporated into a PROTAC molecule, Pomalidomide-PEG1-C2-N3 enables the recruitment of the CRBN E3 ligase to a protein of interest, triggering ubiquitination and subsequent proteasomal degradation of the target protein.

Applications

Pomalidomide-PEG1-C2-N3 is widely used in the field of chemical biology and drug discovery for the synthesis of CRBN-based PROTACs and molecular glues. Its terminal azide group facilitates rapid and efficient bioconjugation with alkyne-containing ligands through click chemistry. Key applications include: construction of heterobifunctional degraders to target disease-related proteins, creation of chemical probes to study protein degradation pathways, and rapid prototyping of new protein degradation modalities. Its modularity makes it compatible with high-throughput library screening and medicinal chemistry optimization, accelerating the discovery of novel protein degraders.