| Size | Price | Stock | Qty |
|---|---|---|---|
| 5mg |
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| 10mg |
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| 25mg |
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| 50mg |
| Targets |
The primary target of KI-696 is KEAP1 (Kelch-like ECH-associated protein 1), which it inhibits by disrupting the KEAP1/NRF2 protein-protein interaction. KEAP1 is a negative regulator of NRF2 (nuclear factor erythroid 2-related factor 2), a transcription factor that controls the expression of antioxidant and cytoprotective genes. Under normal conditions, KEAP1 binds to NRF2 and promotes its degradation. By inhibiting the KEAP1-NRF2 interaction, KI-696 stabilizes NRF2 and allows it to translocate to the nucleus and activate the expression of antioxidant response element (ARE)-containing genes.
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| ln Vitro |
Compound 7, KI696, has a very high affinity for the KEAP1 Kelch domain (ITC Kd=1.3 nM). No significant cross-reactivity is seen with the exception of the organic anion transporting polypeptide 1B1 (OATP1B1) (IC50=2.5 µM), the bile salt export pump BSEP (IC50=4.0 µM), and the phosphodiesterase PDE3A (IC50=10 µM). At dosages up to 10 µM, KI696 does not exhibit any cytotoxicity toward BEAS-2B cells. In normal human bronchial epithelial cells, KI696 stimulates NRF2 nuclear translocation. In non-targeting siRNA-transfected NHBE cells, KI696 enhances the mRNA expression of the NRF2-dependent genes NQO1 and GCLM, whereas compound activity is markedly reduced by NRF2 gene silencing. In a manner that is dependent on NRF2, KI696 raises NQO1 Activity. While pre-treating cells with 1 µM KI696 prior to exposure to tBHP preserved cell shape consistent with the DMSO control, treatment with tBHP obviously had a deleterious effect on cell health and appearance. In bronchial epithelial cells obtained from COPD patients, KI696 Induces the Expression of NRF2-Regulated Genes [1].
KI-696 is a potent and selective inhibitor of the KEAP1/NRF2 interaction. It induces the expression of Nqo1, Ho-1, Txnrd1, Srxn1, Gsta3, and Gclc genes in a dose-dependent manner. These genes are involved in antioxidant defense and cytoprotection. The compound's ability to activate the NRF2 pathway makes it a valuable tool for studying oxidative stress and potential therapeutic applications for diseases involving oxidative stress. KI-696's selectivity for KEAP1 over other proteins contributes to its specificity. |
| ln Vivo |
KI696 promotes the expression of each of the Nqo1, Ho-1, Txnrd1, Srxn1, Gsta3, Gclc genes in a dosage-dependent manner, with maximum increases over vehicle controls of 37-(Nqo1), 17-(Ho-1), 9-(Txnrd1), 28-(Srxn1), 15-(Gsta3) and 13-fold (Gclc) occurring at the 50 µmol/kg dose. EC50 readings are 44.0, 25.7, 42.6, 33.8, 28.4, and 44.1 µmol/ kilogram, respectively, yielding an average EC50 value of 36.4±3.4 µmol/kg. KI696 attenuates ozone-Induced lung inflammation. KI696 reverses ozone-induced reduction of lung GSH levels. KI696 is delivered to rats at 10, 35 and 50 µmol/kg via IV infusion, resulting in steady state chemical concentrations in the blood of 407±44 nM, 946±50 nM and 1437±186 nM, respectively, over the 6 hour infusion period. Exposure to ozone 24 hours post-dose generates a considerable reduction in lung levels of the anti-oxidant molecule, GSH, which is recovered by KI696 in a dose-dependent manner[1].
No specific in vivo activity data is publicly available for KI-696. As a KEAP1-NRF2 interaction inhibitor, it would be expected to activate the NRF2 pathway in vivo. The compound is an excellent tool to study the KEAP1-NRF2 interaction in vivo and has the potential to be used for diseases involving oxidative stress. By activating NRF2, KI-696 could provide protection against oxidative damage in various disease models. However, specific in vivo studies have not been detailed in the available literature. |
| Enzyme Assay |
No specific non-cell assay protocol is available for KI-696. For protein-protein interaction inhibitors, standard cell-free assays include fluorescence polarization, AlphaScreen, or ELISA using recombinant KEAP1 and NRF2 proteins. The compound is incubated with the proteins, and the inhibition of interaction is measured to determine potency. Surface plasmon resonance (SPR) can be used to measure binding affinity and kinetics. These assays provide mechanistic insights into how the compound disrupts the KEAP1-NRF2 interaction.
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| Cell Assay |
No specific cell-based assay protocol is available for KI-696. For KEAP1-NRF2 inhibitors, standard cellular assays involve treatment of cells with the compound and measurement of NRF2 target gene expression. Cells are treated with KI-696 for 6-24 hours, and mRNA levels of NQO1, HO-1, TXNRD1, SRXN1, GSTA3, and GCLC are measured by qPCR. Protein levels of these genes can be assessed by western blot. NRF2 nuclear translocation can be visualized by immunofluorescence. Cell viability assays can be performed to assess cytotoxicity.
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| Animal Protocol |
No specific animal protocol is available for KI-696. For studying the KEAP1-NRF2 pathway in vivo, KI-696 can be administered to animal models of oxidative stress-related diseases. The compound's effects on NRF2 target gene expression in various tissues can be assessed by qPCR or western blot. Disease models such as acute lung injury, ischemia-reperfusion injury, or neuroinflammation could be used to evaluate the compound's protective effects. However, specific protocols have not been detailed in the available literature.
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| ADME/Pharmacokinetics |
No detailed pharmacokinetic data is publicly available for KI-696. The compound has a molecular weight of 550.63 and formula C28H30N4O6S. As a small molecule with moderate lipophilicity, it would be expected to have reasonable oral bioavailability. The compound is a chemical probe for KEAP1, suggesting it has been designed with favorable drug-like properties. Comprehensive pharmacokinetic studies would be required for therapeutic development.
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| Toxicity/Toxicokinetics |
No detailed toxicology data is publicly available for KI-696. As a research compound, standard preclinical toxicology would be required for therapeutic development. The compound's selectivity for KEAP1 may contribute to a manageable safety profile, though chronic activation of NRF2 could have potential long-term effects. The compound is for research use only and not for therapeutic applications.
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| References | |
| Additional Infomation |
KI-696 has the molecular formula C28H30N4O6S and molecular weight 550.63. The chemical name is (S)-3-(7-Methoxy-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)propanoic acid. It is a potent and selective inhibitor of the KEAP1/NRF2 interaction and induces the expression of NQO1, HO-1, TXNRD1, SRXN1, GSTA3, and GCLC genes. No clinical trial status has been identified; it is used as a chemical probe for studying KEAP1-NRF2 biology and oxidative stress.
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| Molecular Formula |
C28H30N4O6S
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|---|---|
| Molecular Weight |
550.626005649567
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| Exact Mass |
550.188
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| CAS # |
1799974-70-1
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| PubChem CID |
118170767
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| Appearance |
White to off-white solid powder
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| LogP |
3.5
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
39
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| Complexity |
962
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| Defined Atom Stereocenter Count |
2
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| SMILES |
S1(C2C=CC=CC=2O[C@H](C)CN1CC1C(C)=CC=C(C=1)[C@H](CC(=O)O)C1C=C(C2=C(C=1)N=NN2C)OC)(=O)=O
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| InChi Key |
ZDNGJXBUEQNFBQ-GCJKJVERSA-N
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| InChi Code |
InChI=1S/C28H30N4O6S/c1-17-9-10-19(22(14-27(33)34)20-12-23-28(25(13-20)37-4)31(3)30-29-23)11-21(17)16-32-15-18(2)38-24-7-5-6-8-26(24)39(32,35)36/h5-13,18,22H,14-16H2,1-4H3,(H,33,34)/t18-,22+/m1/s1
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| Chemical Name |
(S)-3-(7-methoxy-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)propanoic
acid
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| Synonyms |
KI696 KI 696 KI-696
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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 |
| 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) |
DMSO : ~50 mg/mL (~90.81 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (4.54 mM) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (3.78 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8161 mL | 9.0805 mL | 18.1610 mL | |
| 5 mM | 0.3632 mL | 1.8161 mL | 3.6322 mL | |
| 10 mM | 0.1816 mL | 0.9081 mL | 1.8161 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.
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