Pomalidomide 4'-alkylC3-acid

Background Introduction

Pomalidomide 4'-alkylC3-acid is a specialized E3 ligase ligand-linker conjugate designed for the development of proteolysis targeting chimeras (PROTACs) and other targeted protein degradation technologies. This advanced reagent features a pomalidomide core structure that selectively binds the cereblon (CRBN) E3 ubiquitin ligase, functionalized with a 4'-alkyl linker ending in a carboxylic acid (C3-acid) group, which allows flexible conjugation to various warheads or biologically active molecules. Such linkers are essential components for the synthesis of next-generation selective degraders targeting a wide range of disease-related proteins.

Mechanism

Pomalidomide 4'-alkylC3-acid operates by harnessing the ubiquitin-proteasome system through the recruitment of the cereblon (CRBN) E3 ligase. In the context of PROTAC design, the pomalidomide moiety of the conjugate binds to CRBN, while the engineered alkyl linker provides spatial flexibility and the terminal C3-acid offers a reactive handle for covalently attaching target ligands (warheads). When the ligand-linker is joined to a specific protein-targeting moiety, the resulting bifunctional molecule brings the target protein into close proximity with the CRBN ligase. This induced proximity facilitates the ubiquitination and subsequent proteasomal degradation of the target protein, enabling precise and potent elimination of pathogenic or unwanted proteins within cells.

Applications

Pomalidomide 4'-alkylC3-acid serves as a versatile building block for the assembly of custom PROTAC molecules in biomedical research and drug discovery. Its optimized CRBN-binding and flexible linker design are ideal for: 1) Synthesizing PROTACs targeting oncogenic, neurodegenerative, or inflammatory proteins, 2) Exploring the structure-activity relationship (SAR) of linker length and composition in targeted degradation efficacy, 3) Developing molecular glue degraders and hybrid small molecule degraders, 4) Advancing preclinical validation of novel protein targets, and 5) Enabling rapid iteration of degrader molecules in medicinal chemistry and chemical biology applications. Researchers widely use pomalidomide 4'-alkylC3-acid to accelerate their PROTAC pipeline and generate next-generation targeted protein degradation therapeutics.

• Carboxylic acid-functionalized linker improves coupling flexibility for diverse PROTAC designs.
• Engineered for high-yield CRBN E3 ligase ligand conjugation, enabling efficient targeted protein degradation.