1. Product Overview
VH298 (CAS 2097381-85-4), systematically named (2S,4R)-1-((S)-2-(1-cyanocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide, is a potent, cell-permeable, and selective small-molecule inhibitor of the von Hippel–Lindau (VHL) E3 ubiquitin ligase. With the molecular formula C₂₇H₃₃N₅O₄S and a molecular weight of 523.65 g/mol, it appears as a white to off-white or pale pink crystalline solid at room temperature. VH298 disrupts the VHL–HIF-α interaction with a Kd of 80–90 nM (ITC and competitive FP assays), thereby stabilizing hydroxylated HIF-α, inducing HIF-dependent transcription, and activating hypoxic signaling downstream of HIF-α hydroxylation. It is a key chemical probe for hypoxia research and serves as the canonical VHL E3 ligase–recruiting moiety in PROTAC (Proteolysis Targeting Chimera) design. This product is supplied exclusively for laboratory research use and is not intended for clinical, diagnostic, veterinary, food, or cosmetic applications.
2. Key Features and Advantages
• High potency and selectivity: Potent VHL:HIF-α interaction inhibitor with Kd = 80–90 nM; negligible off-target effects against >100 kinases, GPCRs, and ion channels at 50 µM.
• Cell-permeable and non-cytotoxic: Enables robust on-target HIF-α stabilization in cell lines (HeLa, RCC4, etc.) without general cellular toxicity.
• Essential PROTAC building block: Widely used as the VHL ligand in targeted protein degrader design, with well-established synthetic handle and published SAR.
• High purity: Typically ≥98% by HPLC (suppliers also offer >98% or 99%), suitable for cellular assays, Western blot, qPCR, and PROTAC conjugation.
• Good solubility profile: Readily soluble in DMSO (≥50–66 mg/mL), DMF, and ethanol; enables convenient stock preparation (e.g., 10 mM or 100 mM in DMSO).
• Consistent batch quality with supporting analytical data (HPLC, LC-MS, NMR, chiral integrity) available from qualified suppliers; referenced in Nat. Commun. 2016 (Frost et al.) as a validated chemical probe.
3. Main Applications
• Hypoxia and HIF signaling research: Pharmacological stabilization of HIF-α to study hypoxic response, EPO induction, BNIP3/HK2 regulation, and pseudo-hypoxia in cancer and ischemia models.
• PROTAC technology development: Used as the VHL E3 ligase–recruiting ligand to construct bifunctional degraders targeting POIs (e.g., BRD4, BTK, EGFR) via optimized linkers.
• Cell-based assays: Western blot and immunofluorescence to monitor HIF-1α/HIF-2α accumulation; qPCR/RNA-seq for HIF-target gene expression profiling in RCC4, HeLa, HFF, and other cell lines.
• Mechanistic studies on VHL tumor suppressor function, clear cell renal cell carcinoma (ccRCC), and ubiquitin–proteasome pathway regulation.
• General research use as a reference standard or pharmacological probe in medicinal chemistry programs focusing on E3 ligase ligands and targeted protein degradation.
4. Technical Specifications
5. Storage and Handling
• Store the powdered compound sealed with desiccant, protected from light; recommended storage at -20°C (long term: 3 years at -20°C, 2 years at 4°C). For DMSO stock solutions, prepare fresh or aliquot and store at -80°C (6 months stable) or -20°C (1 month); avoid repeated freeze–thaw cycles. Typical working stocks are 10 mM or 100 mM in anhydrous DMSO.
• Before opening, allow the sealed vial to warm to room temperature to prevent moisture condensation. Keep container tightly closed when not in use.
• Handle in a well-ventilated area or fume hood. Use personal protective equipment including safety glasses, nitrile gloves, and a lab coat. Avoid inhalation of dust and contact with skin or eyes.
• Intended exclusively for laboratory research by qualified personnel; not for human or veterinary use, food, drug, or cosmetic applications.
6. Safety Overview
• VH298 is a research chemical with limited toxicological data. Treat as potentially hazardous: may cause irritation to eyes, skin, and respiratory system (WGK 3).
• In case of eye contact, rinse immediately with plenty of running water for at least 15 minutes and seek medical advice. In case of skin contact, wash thoroughly with soap and water.
• If inhaled, move the person to fresh air and keep at rest in a position comfortable for breathing. If ingested, rinse mouth and seek medical attention—do not induce vomiting unless directed by medical personnel.
• Use appropriate engineering controls (fume hood) and personal protective equipment (safety goggles, nitrile gloves, lab coat). Avoid generating dust.
• Dispose of in accordance with local regulations for chemical waste. Do not discharge into drains, waterways, or soil.
• For detailed safety information, refer to the applicable Safety Data Sheet (SDS) prior to handling.
