N-[(1-Fluorocyclopropyl)carbonyl]-3-Methyl-L-Valyl-(4r)-4-Hydroxy-N-[4-(4-Methyl-1,3-Thiazol-5-Yl)benzyl]-L-Prolinamide

Background Introduction

N-[(1-Fluorocyclopropyl)carbonyl]-3-Methyl-L-Valyl-(4r)-4-Hydroxy-N-[4-(4-Methyl-1,3-Thiazol-5-Yl)benzyl]-L-Prolinamide is a highly specialized E3 ligase ligand, designed to recruit the Von Hippel-Lindau (VHL) E3 ubiquitin ligase complex. VHL-recruiting ligands are essential building blocks in the assembly of Proteolysis Targeting Chimeras (PROTACs), which facilitate targeted protein degradation as an innovative modality in drug discovery. This ligand features an optimized proline core and functionalized side chains for high binding affinity, metabolic stability, and modular conjugation, making it ideal for advanced chemical biology applications.

Mechanism

This compound acts as a VHL E3 ubiquitin ligase ligand by mimicking the natural HIF-1α (hypoxia-inducible factor 1-alpha) degradation motif, thereby engaging the VHL E3 ligase complex. When incorporated into a bifunctional PROTAC molecule—where one end binds the target protein and the other recruits VHL—it promotes the proximity-driven ubiquitination of the target protein. The presence of a fluorinated cyclopropyl group and a thiazole-containing benzyl moiety enhances both the specificity and binding affinity for the VHL interface, supporting efficient and selective protein degradation via the ubiquitin-proteasome system.

Applications

N-[(1-Fluorocyclopropyl)carbonyl]-3-Methyl-L-Valyl-(4r)-4-Hydroxy-N-[4-(4-Methyl-1,3-Thiazol-5-Yl)benzyl]-L-Prolinamide is widely used as a crucial linker and warhead for VHL-based PROTAC synthesis. Its optimized structure allows medicinal chemists and researchers to develop PROTAC molecules targeting a broad range of disease-relevant proteins. Key applications include:

• Construction of VHL E3 ligase recruiting elements in PROTAC libraries for drug discovery
• Development of next-generation degraders for oncology, immunology, and neurodegenerative research
• Target validation through chemical knockdown of undruggable or novel proteins
• Structure-activity relationship (SAR) studies to enhance PROTAC efficacy and selectivity
• Academic and CRO-supported custom PROTAC synthesis projects focused on protein degradation technology

• High-purity compound verified by HPLC, NMR, and LC-MS
• Consistent batch-to-batch reproducibility with complete QC documentation
• Supplied with COA, MSDS, and analytical data for traceability
• Reliable global shipping with stability-guaranteed packaging
• Dedicated technical support and optional custom synthesis service
• Demonstrates strong binding affinity to CRBN, VHL, or other E3 ligases
• Enables stable E3 ligase recruitment for targeted protein degradation
• High-affinity ligand specifically targets VHL E3 ligase, enabling effective ubiquitination of protein of interest in PROTAC applications.
• Optimized structure enhances PROTAC cell permeability and metabolic stability, supporting development of potent targeted protein degradation therapies.