(2S,4R)-1-[(2S)-2-acetamido-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-3-(methylamino)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]-3-oxopropyl]pyrrolidine-2-carboxamide

Background Introduction

(2S,4R)-1-[(2S)-2-acetamido-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-3-(methylamino)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]-3-oxopropyl]pyrrolidine-2-carboxamide is an advanced ligand designed for targeting the von Hippel-Lindau (VHL) E3 ubiquitin ligase. VHL ligands are frequently employed in the rational design of heterobifunctional molecules, including PROTACs (Proteolysis Targeting Chimeras), due to their high specificity and efficiency in recruiting the VHL complex. This compound incorporates structural modifications for improved aqueous solubility, cellular permeability, and effective conjugation to various target protein ligands, facilitating the generation of next-generation protein degraders.

Mechanism

Acting as a high-affinity ligand for the VHL E3 ligase complex, the compound binds selectively to the VHL protein, a substrate recognition unit of the CUL2-VHL E3 ubiquitin ligase. In a PROTAC design, one end of the molecule is tethered to this VHL ligand, while the other end is linked to a ligand for the protein of interest. This proximity enables the E3 ligase to transfer ubiquitin molecules to the target protein, flagging it for rapid degradation by the 26S proteasome. The optimized stereochemistry and side-chain functionalities of this VHL ligand ensure efficient recruitment and precise orientation of the degradation machinery.

Applications

This VHL E3 ligase ligand is widely used in the synthesis of VHL-based PROTACs for targeted protein degradation, drug discovery, and chemical biology applications. Its key applications include:

• Assembly of highly potent and selective PROTACs for degradation of disease-relevant proteins
• Structure-activity relationship (SAR) studies in PROTAC optimization campaigns
• Development of novel chemical probes to elucidate protein function via targeted degradation
• Academic and pharmaceutical research focused on undruggable targets using TPD strategies

This compound is also suitable for custom conjugation projects, allowing researchers to design and optimize VHL-directed degraders for a wide range of biological targets.

• 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 VHL E3 ligase ligand enables potent and selective target protein degradation in PROTAC design.
• Optimized stereochemistry enhances binding efficiency and cellular permeability, making it ideal for advanced drug discovery projects.