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TBK1/IKKε-IN-5 (compound 1 in patent WO 2016049211) is a potent dual TBK1 and IKKε inhibitor, has an IC50 of 1 nM and 5.6 nM for TBK1 and IKK, respectively.
Targets |
TBK1 (IC50 = 1 nM); IKKε (IC50 = 5.6 nM)
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ln Vitro |
TBK1/IKKε-IN-1(compound 1) efficiently inhibits the production of immune suppressive cytokines by CT26 cell line spheroids without causing cytotoxic effects and increases the secretion of IL-2 and IFN-γ from purified CD4+ and CD8+ T cells from healthy human donors as well as IL-2 from Jurkat human T-cell leukemia cells. Ex vivo addition of TBK1/IKKε-IN-1(compound 1) to PD-1 blockade improves killing of CT26 MDOTS, which is accompanied by decreased levels of CCL4, CCL3, and IL-1β and induction of cytokines involved in activated innate immune responses. [1]
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ln Vivo |
TBK1/IKKε-IN-1(compound 1)±anti-PD-L1 is administered to Balb/c mice bearing CT26 tumors. Greater tumor control and longer survival are evident with TBK1/IKKε-IN-1(compound 1) + anti-PD-L1 compared to TBK1/IKKε-IN-1(compound 1) or anti-PD-L1 alone, which is in line with MDOTS profiling data. Reimplantation of CT26 into mice with exceptional responses to combination therapy causes no growth, whereas EMT-6 implanted tumors grow normally. This finding suggests that mice treated with TBK1/IKKε-IN-1(compound 1) + anti-PD-L1 have CT26 cells that have been induced to form an immunologic memory. Because of this, MDOTS profiling successfully mimics the in vivo response to PD-1 blockade +/− TBK1/IKKε inhibition, highlighting the potential of ex vivo screening in MDOTS to create combination immunotherapies. [1]
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Cell Assay |
Analyses of interleukin-2 and interferon gammaFreshly isolated human CD4+ and CD8+ T cells are spun down, resuspended in serum-free X-vivo15 media, supplemented with 5 ng/mL IL-17, and incubated overnight at 37°C. Cells are plated on anti-CD3 coated plates with 2 μg/mL anti-CD28. For 24 hours for IL-2 and 96 hours for IFNγ, cells are treated in replicate plates with a dose-titration of TBK1/IKKε-IN-1(compound 1). Using single- or multi-plex immunoassay, the levels of IL-2 and IFNγ in the supernatant are determined. A dose titration of TBK1/IKKε-IN-1(compound 1) is applied to Jurkat T cell leukemia cells that have been plated on anti-CD3 coated plates for 24 hours.
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Animal Protocol |
11-12 week old female Balb/c mice implanted with 1×106 CT26 colon carcinoma cells.
40 mg/kg Oral gavage |
References |
Molecular Formula |
C₂₈H₃₁N₇O₃
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Molecular Weight |
513.59
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Exact Mass |
513.25
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Elemental Analysis |
C, 65.48; H, 6.08; N, 19.09; O, 9.35
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CAS # |
1893397-65-3
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Related CAS # |
1893397-65-3
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Appearance |
Solid powder
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SMILES |
C1COCCC1OC2=C(C=C(C=C2)C3=NC(=NC=N3)NC4=CC=C(C=C4)N5CCN(CC5)C6COC6)C#N
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InChi Key |
QYQFLAQHGHBIFA-UHFFFAOYSA-N
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InChi Code |
InChI=1S/C28H31N7O3/c29-16-21-15-20(1-6-26(21)38-25-7-13-36-14-8-25)27-30-19-31-28(33-27)32-22-2-4-23(5-3-22)34-9-11-35(12-10-34)24-17-37-18-24/h1-6,15,19,24-25H,7-14,17-18H2,(H,30,31,32,33)
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Chemical Name |
2-(oxan-4-yloxy)-5-[4-[4-[4-(oxetan-3-yl)piperazin-1-yl]anilino]-1,3,5-triazin-2-yl]benzonitrile
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Synonyms |
TBK1/IKKε-IN-5; QUN97653; QUN 97653; QUN-97653
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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: 5~7.8 mg/mL (9.7~15.2 mM)
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Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80: Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 :Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400  (Please use freshly prepared in vivo formulations for optimal results.) |
Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
1 mM | 1.9471 mL | 9.7354 mL | 19.4708 mL | |
5 mM | 0.3894 mL | 1.9471 mL | 3.8942 mL | |
10 mM | 0.1947 mL | 0.9735 mL | 1.9471 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.
Characterization of Compound 1, a Novel TBK1/IKKε inhibitor. Cancer Discov . 2018 Feb;8(2):196-215. td> |
TBK1/IKKε inhibition enhances response to PD-1 blockade. Cancer Discov . 2018 Feb;8(2):196-215. td> |