(2S,4R)-1-[(2S)-2-acetamido-3,3-dimethylbutanoyl]-N-[(1S)-1-(4-ethynylphenyl)ethyl]-4-hydroxypyrrolidine-2-carboxamide

Background Introduction

(2S,4R)-1-[(2S)-2-acetamido-3,3-dimethylbutanoyl]-N-[(1S)-1-(4-ethynylphenyl)ethyl]-4-hydroxypyrrolidine-2-carboxamide is a high-affinity ligand specifically designed to target the von Hippel-Lindau (VHL) E3 ubiquitin ligase, a frequently used E3 ligase in the creation of PROTACs (Proteolysis Targeting Chimeras). The incorporation of functionalized groups such as the ethynyl handle and the acetamido-masked tert-leucine residue provides optimized properties for linker attachment, compatibility with click chemistry, and facilitates the construction of next-generation PROTAC molecules for targeted protein degradation.

Mechanism

This compound operates as a VHL-binding E3 ligase ligand, leveraging its stereochemically defined pyrrolidine core to mimic hypoxia-inducible factor 1α (HIF-1α) peptide motifs that are naturally recognized by VHL. Upon engagement, the ligand recruits the VHL E3 ligase complex, allowing for the proximity-induced ubiquitination and subsequent degradation of target proteins in the presence of a bifunctional PROTAC molecule. The ethynyl group at the para-position on the phenyl ring offers a versatile chemical handle for bioorthogonal conjugation, enabling rapid and efficient PROTAC assembly with a wide range of warhead ligands.

Applications

(2S,4R)-1-[(2S)-2-acetamido-3,3-dimethylbutanoyl]-N-[(1S)-1-(4-ethynylphenyl)ethyl]-4-hydroxypyrrolidine-2-carboxamide is widely applied in the design and synthesis of VHL-based PROTACs for targeted protein degradation in chemical biology and drug discovery. Its optimized structure and compatibility with click chemistry greatly simplify the preparation of bifunctional molecules and SAR libraries. Primary applications include:

• Construction of VHL E3 ligase-recruiting elements in PROTACs
• Development of novel degraders for challenging therapeutic targets
• Validation of target proteins through knockdown studies
• Streamlined medicinal chemistry for custom conjugates, PROTAC tool compounds, and CRO synthesis strategies

• 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
• Highly selective VHL ligand for targeted protein degradation via the ubiquitin-proteasome system.
• Versatile building block for designing potent, cell-permeable VHL-based PROTACs.