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| 5mg |
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Purity: ≥98%
BI605906 (BI-605906) is a novel and potent IKKβ inhibitor with anti-Inflammatory Effects. It inhibits IKKβ with an IC50 value of 380 nM when assayed at 0.1 mM ATP. The pro-inflammatory mediators IL-6, IL-1b, and CXCL1/2 are inhibited by BI605906 by blocking the TNFα-dependent degradation of I-B. In primary hepatocytes from healthy animals, metformin and the IKKβ (inhibitor of kappa B kinase) inhibitor BI605906 both prevented tumor necrosis factor-α-dependent IκB degradation and the expression of the proinflammatory mediators interleukin-6, interleukin-1β, and CXCL1/2. Since BI605906 did not mimic the effects of metformin on the expression of lipogenic genes, glucose production, or AMP-activated protein kinase, it was possible to distinguish between the effect of metformin on IKKα/β suppression and some metabolic actions.
| Targets |
IKKβ (IC50 = 380 nM)
Inhibitor of kappa B kinase beta (IKKβ). It is described as a specific IKKβ inhibitor, |
|---|---|
| ln Vitro |
In primary mouse hepatocytes, BI-605906 (10 µM) inhibited tumor necrosis factor-α (TNF-α)-induced degradation of the NF-κB negative regulator IκB, comparable to the effect of metformin (2 mM).
Unlike metformin, BI-605906 (10 µM) did not suppress signaling downstream of the mammalian target of rapamycin (mTOR), as evidenced by a lack of effect on phospho-S6 and phospho-p70 S6 kinase levels. BI-605906 (10 µM) did not activate AMP-activated protein kinase (AMPK) in hepatocytes, unlike metformin. BI-605906 (10 µM) strongly inhibited TNF-α-dependent gene expression of proinflammatory mediators CINC-1/CXCL1, CXCL2, IL-1β, and IL-6 in primary mouse hepatocytes. Co-incubation of BI-605906 (10 µM) with TNF-α in hepatocytes increased the mRNA expression of lipogenic genes (sterol regulatory element-binding protein 1c, peroxisome proliferator-activated receptor-γ, and fatty acid synthase), in contrast to metformin which reduced their expression. BI-605906 alone did not alter the expression of these genes. BI-605906 (10 µM) did not mimic the effect of metformin on suppressing basal or cytokine-stimulated hepatic glucose production in primary mouse hepatocytes. |
| Cell Assay |
Primary hepatocytes are cultured in serum-free medium for an overnight period before being stimulated for 3 hours with or without 2 mM TNF-α and Metformin. Additionally, before cell lysis and immunoblotting, cells are incubated with or without 10 μM BI605906 or 100 nM Rapamycin[2].
Primary Mouse Hepatocyte Culture and Treatment: Primary mouse hepatocytes were extracted from mice. For signaling studies, cells were incubated in serum-free medium overnight and then stimulated with or without drugs (e.g., 10 µM BI-605906, 2 mM metformin) for 3 hours. For the last 15 minutes, cells were treated with or without 10 ng/mL TNF-α. Cells were then lysed, and proteins were analyzed by immunoblotting using specific antibodies. Gene Expression Analysis in Hepatocytes: Primary mouse hepatocytes were treated with or without 10 ng/mL TNF-α, 2 mM metformin, or 10 µM BI-605906 for 8 hours. Cells were then lysed, total RNA was extracted, and cDNA was synthesized. mRNA expression of target genes (IL-6, CXCL1, IL-1β, CXCL2, lipogenic genes) was quantified by real-time polymerase chain reaction (RT-PCR) using specific primer/probe sets. Expression was calculated relative to a housekeeping gene. Hepatocyte Glucose Production Assay: Primary mouse hepatocytes were plated and treated with or without drugs/cytokines for 12 hours in glucose-free medium supplemented with lactate/pyruvate and dexamethasone. At the end of the incubation, medium was collected, and glucose concentration was determined using a glucose oxidase-based assay. |
| References | |
| Additional Infomation |
This study used BI-605906 as a specific pharmacological tool to inhibit the IKKβ/NF-κB pathway, enabling researchers to elucidate the anti-inflammatory mechanism of metformin. The study concluded that although both metformin and BI-605906 inhibit inflammatory signaling pathways (IκB degradation, pro-inflammatory cytokine expression), their effects on metabolic pathways (AMPK activation, mTOR signaling pathway, adipogenesis gene expression, glucose production) are quite different. This suggests that the anti-inflammatory effect of metformin can be distinguished from some of its metabolic effects. BI-605906 was generously provided by Sir Philip Cohen of the University of Dundee.
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| Molecular Formula |
C17H22N4O3F2S2
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|---|---|
| Molecular Weight |
432.50838
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| Exact Mass |
432.11
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| Elemental Analysis |
C, 47.21; H, 5.13; F, 8.79; N, 12.95; O, 11.10; S, 14.83
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| CAS # |
960293-88-3
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| Related CAS # |
960293-88-3
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| PubChem CID |
23652660
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| Appearance |
Light yellow to yellow solid powder
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| Density |
1.48±0.1 g/cm3 (20 °C, 760 mmHg)
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| Boiling Point |
713.7±60.0 °C (760 mmHg)
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| LogP |
4.919
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
28
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| Complexity |
695
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C(C1=C(N)C2C(=NC(N3CCC(S(C)(=O)=O)CC3)=CC=2C(CC)(F)F)S1)N
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| InChi Key |
IYHHRZBKXXKDDY-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C17H22F2N4O3S2/c1-3-17(18,19)10-8-11(23-6-4-9(5-7-23)28(2,25)26)22-16-12(10)13(20)14(27-16)15(21)24/h8-9H,3-7,20H2,1-2H3,(H2,21,24)
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| Chemical Name |
3-amino-4-(1,1-difluoropropyl)-6-(4-methylsulfonylpiperidin-1-yl)thieno[2,3-b]pyridine-2-carboxamide
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| Synonyms |
BI 605906; BI-605906; BI605906
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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 (~115.6 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 1.25 mg/mL (2.89 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 12.5 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: 1.25 mg/mL (2.89 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 12.5 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3121 mL | 11.5604 mL | 23.1209 mL | |
| 5 mM | 0.4624 mL | 2.3121 mL | 4.6242 mL | |
| 10 mM | 0.2312 mL | 1.1560 mL | 2.3121 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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