(4R)-3-Methyl-L-valyl-4-hydroxy-N-[[4-(4-methyl-5-thiazolyl)phenyl]methyl]-L-prolinamide hydrochloride (1:1)
[CAS# 1448189-80-7]

Identification

• Classification: API >> Inhibitor drug
• Name: (4R)-3-Methyl-L-valyl-4-hydroxy-N-[[4-(4-methyl-5-thiazolyl)phenyl]methyl]-L-prolinamide hydrochloride (1:1)
• Synonyms: (S,R,S)-AHPC hydrochloride;VHL Ligand 1 (hydrochloride)
• Protein Sequence: XX
• Molecular Formula: C₂₂H₃₀N₄O₃S^.HCl
• Molecular Weight: 467.03
• CAS Registry Number: 1448189-80-7
• SMILES: CC1=C(SC=N1)C2=CC=C(C=C2)CNC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)N)O.Cl

Properties

• Solubility: 100 mM (water), 100 mM (DMSO)

Safety Data

• Hazard Symbols: GHS07 Warning
• Hazard Statements: H302-H315-H319-H335
• Precautionary Statements: P261-P305+P351+P338

Discovory and Applicatios

(S,R,S)-AHPC hydrochloride is a compound known for its role in targeted protein degradation, a revolutionary approach in drug development and biomedical research. This compound, also known as ARV-771 hydrochloride, is used in the development of proteolysis targeting chimeras (PROTACs), which offer a new strategy for modulating protein function within cells. The discovery of (S,R,S)-AHPC hydrochloride stems from the ongoing search for innovative ways to modulate protein levels within cells. This compound was developed as part of research into PROTAC technology, which aims to selectively degrade pathogenic proteins by exploiting the cell's natural protein degradation machinery.

(S,R,S)-AHPC hydrochloride is a PROTAC linker synthesized through a series of chemical reactions that introduce stereospecific elements into the molecule, ensuring its correct three-dimensional structure. The synthesis typically involves the construction of a chiral scaffold, which is then functionalized with amide, hydroxyl, and linker groups to facilitate its binding to the target protein and the E3 ubiquitin ligase complex.

(S,R,S)-AHPC hydrochloride is characterized by its ability to induce protein degradation. The chemical structure includes a specific stereochemistry (S, R, S configuration) that is critical for its biological activity. It functions as a bifunctional molecule, meaning that it has two distinct ends: one end binds to the target protein, while the other end recruits the E3 ubiquitin ligase, leading to proteasomal ubiquitination and subsequent degradation of the target protein.

The main application of (S,R,S)-AHPC hydrochloride is targeted protein degradation via PROTACs. PROTACs are bifunctional molecules that hijack the ubiquitin-proteasome system of the cell to selectively degrade unwanted or harmful proteins. By binding to the target protein and the E3 ligase, (S,R,S)-AHPC hydrochloride promotes ubiquitination of the target protein, marking it for proteasomal destruction.

In cancer therapy, PROTACs based on (S,R,S)-AHPC hydrochloride are used to degrade oncogenic proteins that drive tumor growth. For example, it has been used to degrade bromodomain and extra-terminal (BET) proteins, which are involved in transcriptional regulation and are often overexpressed in cancer. This degradation stops cancer cells from proliferating by removing key proteins that are essential for their survival.

In neurodegenerative diseases, (S,R,S)-AHPC hydrochloride is being studied intensively for its potential to target and degrade misfolded or toxic proteins that accumulate in diseases such as Alzheimer's or Parkinson's. By eliminating these pathogenic proteins, PROTACs can mitigate the harmful effects of their accumulation in neurons.

(S,R,S)-AHPC hydrochloride is also being investigated for use in infectious diseases, where degradation of viral or bacterial proteins could inhibit pathogen replication and improve disease outcomes.

The development of (S,R,S)-AHPC hydrochloride paves the way for new therapeutics based on targeted protein degradation. Ongoing studies are aimed at optimizing its binding specificity, improving its pharmacokinetic properties, and expanding its use to target more proteins associated with various diseases. Researchers are also investigating its potential in combination therapies, where it can be used with traditional drugs to enhance efficacy.

References

2022. Designing Soluble PROTACs: Strategies and Preliminary Guidelines. Journal of Medicinal Chemistry, 65(10).
DOI: 10.1021/acs.jmedchem.2c00201

2024. Radiation responsive PROTAC nanoparticles for tumor-specific proteolysis enhanced radiotherapy. Journal of Materials Chemistry B, 12(14).
DOI: 10.1039/D3TB03046F

2022. E3 ligase ligand chemistries: from building blocks to protein degraders. Chemical Society Reviews, 51(9).
DOI: 10.1039/D2CS00148A