Pomalidomide-C6-COOH

Background Introduction

Pomalidomide-C6-COOH is a specialized E3 ligase ligand-linker conjugate, serving as a crucial building block in the rational design of PROTACs (Proteolysis Targeting Chimeras) and other targeted protein degradation technologies. Pomalidomide, a derivative of thalidomide, acts as a high-affinity ligand for the E3 ubiquitin ligase cereblon (CRBN), and the C6-COOH (carboxyl-hexyl) linker provides an optimized length and functional handle for efficient conjugation with various ligands tailored to designated protein targets.

Mechanism

The mechanism of action for Pomalidomide-C6-COOH is rooted in its dual functionality. The pomalidomide moiety specifically binds to the cereblon (CRBN) component of the E3 ubiquitin ligase complex, recruiting the ligase machinery. The C6-COOH linker extends from the ligase ligand and features a carboxylic acid group, ideal for downstream coupling to other molecules—such as a ligand for a desired protein of interest (POI). Upon assembly into a bifunctional PROTAC molecule, the conjugate binds both CRBN and the POI, facilitating the transfer of ubiquitin molecules onto the POI. This marks the target protein for proteasomal degradation, resulting in a selective and catalytic downregulation of the POI inside cells.

Applications

Pomalidomide-C6-COOH is extensively used in the development and synthesis of PROTACs that exploit CRBN as the recruiting E3 ligase. Its structure allows medicinal chemists to rapidly generate custom bifunctional molecules for targeted protein degradation therapies, enabling the study and therapeutic modulation of previously 'undruggable' proteins. Applications include preclinical research into disease-relevant protein targets, structure-activity relationship (SAR) studies for protein degraders, chemical biology investigations, and the development of next-generation therapeutics for oncology, neurodegenerative diseases, and immune disorders.