Pomalidomide-linker 3

Background Introduction

Pomalidomide-linker 3 is a bifunctional synthetic reagent used in targeted protein degradation studies, particularly in the development of PROTACs (Proteolysis Targeting Chimeras). Derived from pomalidomide, an immunomodulatory drug (IMiD), this conjugate features a linker moiety designed for efficient chemistry with a ligand against your protein of interest. The modular nature of pomalidomide-linker 3 streamlines the creation of heterobifunctional molecules for selective protein knockdown.

Mechanism

Pomalidomide-linker 3 functions as an E3 ligase ligand-linker conjugate. The pomalidomide portion is recognized by the cereblon (CRBN) E3 ubiquitin ligase complex. When incorporated into a PROTAC molecule, the linker connects pomalidomide to another ligand that binds a target protein. This brings the target protein into close proximity with the E3 ligase, enabling ubiquitination and subsequent degradation by the proteasome. The efficient and stable linker design ensures proper spatial orientation for optimal ternary complex formation and activity.

Applications

Pomalidomide-linker 3 is widely used in chemical biology and drug discovery research, particularly for: (1) Design and synthesis of CRBN-recruiting PROTACs targeting diverse proteins for degradation; (2) Exploratory studies on protein function and validation of potential therapeutic targets in oncology, neurodegeneration, and immunology; (3) Development of next-generation therapeutics overcoming resistance to classical small-molecule inhibitors; and (4) Evaluation of linker optimisation strategies to improve pharmacokinetics and cellular permeability of PROTACs. It is a crucial building block for researchers aiming to harness targeted protein degradation technologies.