Pomalidomide-PEG1-C2-NH2

Background Introduction

Pomalidomide-PEG1-C2-NH2 is a versatile E3 ligase ligand-linker conjugate commonly used in the development of targeted protein degradation therapies, particularly PROTACs (Proteolysis Targeting Chimeras). By combining pomalidomide—an immunomodulatory drug that recruits the E3 ligase cereblon (CRBN)—with a polyethylene glycol (PEG1) spacer and a C2-amino linker, this molecule provides a reliable and modular platform for attaching protein-targeting ligands, which enables the creation of custom PROTAC molecules.

Mechanism

Pomalidomide-PEG1-C2-NH2 functions as a bifunctional tool in PROTAC design. The pomalidomide moiety binds selectively to the CRBN E3 ubiquitin ligase, recruiting this complex to the target protein. The PEG1-C2 linker offers rigidity and optimal spacing for effective ubiquitination. When the C2-amino linker is conjugated to a ligand specific for a target protein, the resulting PROTAC molecule brings the target protein into proximity with the CRBN E3 ligase, promoting polyubiquitination and subsequent proteasomal degradation of the target protein. This provides a catalytic, event-driven mode of action, in contrast to traditional inhibition.

Applications

Pomalidomide-PEG1-C2-NH2 is widely used in the synthesis of PROTACs designed to selectively degrade disease-causing proteins involved in cancer, neurodegeneration, and immunological disorders. It serves as a key building block for researchers developing next-generation targeted therapies, enabling rapid construction and evaluation of various PROTAC candidates. Additionally, its modular design is suitable for in vitro and in vivo studies, structure-activity relationship (SAR) exploration, and high-throughput screening campaigns in drug discovery.