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Purity: ≥98%
Description: VH-298 is a novel and highly potent inhibitor of the VHL:HIF-α protein-protein interaction with a Kd value of 80 to 90 nM, and has been used in PROTAC technology. Chemical strategies to using small molecules to stimulate hypoxia inducible factors (HIFs) activity and trigger a hypoxic response under normoxic conditions, such as iron chelators and inhibitors of prolyl hydroxylase domain (PHD) enzymes, have broad-spectrum activities and off-target effects. VH298 is a potent VHL inhibitor that stabilizes HIF-α and elicits a hypoxic response via a different mechanism, that is the blockade of the VHL:HIF-α protein-protein interaction downstream of HIF-α hydroxylation by PHD enzymes. VH298 engages with high affinity and specificity with VHL as its only major cellular target, leading to selective on-target accumulation of hydroxylated HIF-α in a concentration- and time-dependent fashion in different cell lines, with subsequent upregulation of HIF-target genes at both mRNA and protein levels. VH298 represents a high-quality chemical probe of the HIF signalling cascade and an attractive starting point to the development of potential new therapeutics targeting hypoxia signalling.
| ln Vitro |
By obstructing the VHL, the powerful, non-toxic, and cell-permeable chemical probe VH-298 causes the hypoxic response. With Kd values of 90 and 80 nM in isothermal titration calorimetry and competitive fluorescence polarization assay, VH-298 is a highly powerful inhibitor of the VHL:HIF-α interaction. VH-298 quickly binds to the VHL complex and takes time to disassociate. When VH-298 is used at a 50 μM concentration, it barely affects more than 100 evaluated cellular kinases, GPCRs, and ion channels in vitro. Cells can pass through VH-298 and it is not hazardous to them. VH-298's permeability is determined to be 19.4 nm s -1 through measurement. VH-298 causes hydroxylated HIF-α to accumulate on-target in a concentration- and time-dependent manner in human cell lines, such as HeLa cancer cells and renal cell carcinoma 4 (RCC4) cells. VH-298 raises EPO mRNA levels by 2.5 times in RCC4-HA-VHL but not in VHL-null RCC4-HA, suggesting that endogenous EPO synthesis can be stimulated by pharmacological inhibition of VHL. While VH-298 and hypoxia both work well to raise PHD2 and HK2 protein levels, in HFF, VH-298 therapy causes a greater increase in BNIP3 protein levels than hypoxia treatment[1].
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| References |
[1]. Frost J, et al. Potent and selective chemical probe of hypoxic signalling downstream of HIF-α hydroxylation via VHL inhibition. Nat Commun. 2016 Nov 4;7:13312
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| Molecular Formula |
C27H33N5O4S
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| Molecular Weight |
523.65
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| CAS # |
2097381-85-4
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| Appearance |
Typically exists as solids (or liquids in special cases) at room temperature
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| SMILES |
O=C([ C@H]1N(C([C@@H](NC(C2(CC2)C#N)=O)C(C)(C)C)=O)C[ C@H](O)C1)NCC3=CC=C(C4=C(C)N=CS4)C=C3
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| Chemical Name |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.77 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (4.77 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (4.77 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9097 mL | 9.5484 mL | 19.0967 mL | |
| 5 mM | 0.3819 mL | 1.9097 mL | 3.8193 mL | |
| 10 mM | 0.1910 mL | 0.9548 mL | 1.9097 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
Biophysical and structural characterization of VH298, a new potent VHL inhibitor.. From: Potent and selective chemical probe of hypoxic signalling downstream of HIF-α hydroxylation via VHL inhibition.Nat Commun.2016 Nov 4;7:13312. |
VH298 induces concentration- and time-dependent on-target specific accumulation of hydroxylated HIF-α in human cell lines.. From: Potent and selective chemical probe of hypoxic signalling downstream of HIF-α hydroxylation via VHL inhibition.Nat Commun.2016 Nov 4;7:13312. |
VHL inhibitors induce HIF-α transcriptional activity in various cell lines.. From: Potent and selective chemical probe of hypoxic signalling downstream of HIF-α hydroxylation via VHL inhibition.Nat Commun.2016 Nov 4;7:13312. |
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