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Purity: ≥98%
Takinib is a novel, potent and selective TAK1 inhibitor with an IC50 of 9.5 nM. Takinib induces apoptosis following TNF-α stimulation in cell models of rheumatoid arthritis and metastatic breast cancer. Takinib is an inhibitor of autophosphorylated and non-phosphorylated TAK1 that binds within the ATP-binding pocket and inhibits by slowing down the rate-limiting step of TAK1 activation. Overall, Takinib is an attractive starting point for the development of inhibitors that sensitize cells to TNF-α-induced cell death, with general implications for cancer and autoimmune disease treatment. Tumor necrosis factor alpha (TNF-α) has both positive and negative roles in human disease. In certain cancers, TNF-α is infused locally to promote tumor regression, but dose-limiting inflammatory effects limit broader utility. In autoimmune disease, anti-TNF-α antibodies control inflammation in most patients, but these benefits are offset during chronic treatment. TAK1 acts as a key mediator between survival and cell death in TNF-α-mediated signaling.
| ln Vitro |
After TNF-α activation, tikinib (10–10,000 nM; 24 hours) causes MDA-MB-231 cells to undergo apoptosis [1]. Takinib (10 μM; 0–1 hour) decreases p65 and IKK phosphorylation [1]. The chemical foundation for PfPK9 (KD(app) 0.46 μM) malaria inhibitor development is provided by tikinib [3]. TAK1Thr184/187, STAT3Tyr705, and STAT3Ser727 phosphorylation are induced in RASF treated with IL-1β (10 ng/mL; 30 minutes) by tikinib (2 hours; 0.1-20 μM; human RASF) [4].
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| ln Vivo |
In a mouse model of type II collagen-induced arthritis (CIA) of rheumatoid arthritis, tikinib (50 mg/kg; i.p.; once daily on days 18–36) lowers clinical scores [4]. ?In Hodgkin's lymphoma xenografted NSG mice, takinib (50 mg/kg; oral gavage; daily till day 17) inhibits the formation of tumors [5].
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| Cell Assay |
Western Blot Analysis[1]
Cell Types: Breast cancer cell line MDA-MB-231 Tested Concentrations: 10 μM Incubation Duration: 5, 15, 30, 60 minutes Experimental Results: IKK and p65 were maximally phosphorylated at 15 minutes, indicating activation of NF -κB pathway, whereas p38 phosphorylation peaked at 30 min. Western Blot Analysis[4] Cell Types: IL-1β treatment (10 ng/mL; 30 minutes) RASF Tested Concentrations: 0.1-20 µM Incubation Duration: 2 hrs (hours) Experimental Results: Induction of TAK1Thr184/187, STAT3Tyr705 and STAT3Ser727 phosphorylation. |
| Animal Protocol |
Animal/Disease Models: Male DBA/1 mouse (CIA arthritis model) [4]
Doses: 50 mg/kg Route of Administration: intraperitoneal (ip) injection; one time/day starting on days 18-36 Experimental Results: compared to vehicle control , clinical arthritis scores diminished. Animal/Disease Models: Female NSG mice (8 weeks old) [5] Doses: 50 mg/kg Route of Administration: po (oral gavage); one time/day until 17 days Experimental Results: Tumor growth slowed down and tumor size/weight diminished. |
| References |
[1]. Totzke J, et al. Takinib, a Selective TAK1 Inhibitor, Broadens the Therapeutic Efficacy of TNF-α Inhibition for Cancer and Autoimmune Disease. Cell Chem Biol. 2017 Aug 17;24(8):1029-1039.
[2]. Scarneo SA, et.al. Pharmacological inhibition of TAK1, with the selective inhibitor takinib, alleviates clinical manifestation of arthritis in CIA mice. Arthritis Res Ther. 2019 Dec 17;21(1):292. [3]. Raphemot R, et al. Plasmodium PK9 Inhibitors Promote Growth of Liver-Stage Parasites. Cell Chem Biol. 2019 Mar 21;26(3):411-419.e7. [4]. Panipinto PM, et.al. Takinib Inhibits Inflammation in Human Rheumatoid Arthritis Synovial Fibroblasts by Targeting the Janus Kinase-Signal Transducer and Activator of Transcription 3 (JAK/STAT3) Pathway. Int J Mol Sci. 2021;22(22):12580. Published 2021 Nov 22. [5]. Song Z,et.al. Essential role of the linear ubiquitin chain assembly complex and TAK1 kinase in A20 mutant Hodgkin lymphoma. Proc Natl Acad Sci U S A. 2020 Nov 17;117(46):28980-28991. |
| Molecular Formula |
C18H18N4O2
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|---|---|
| Molecular Weight |
322.3611
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| CAS # |
1111556-37-6
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| SMILES |
O=C(C1=CC=CC(C(NC2=NC3=CC=CC=C3N2CCC)=O)=C1)N
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| InChi Key |
UOZVVPXKJGOFIG-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C18H18N4O2/c1-2-10-22-15-9-4-3-8-14(15)20-18(22)21-17(24)13-7-5-6-12(11-13)16(19)23/h3-9,11H,2,10H2,1H3,(H2,19,23)(H,20,21,24)
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| Chemical Name |
3-N-(1-Propylbenzimidazol-2-yl)benzene-1,3-dicarboxamide
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| Synonyms |
EDHS-206; EDHS 206; EDHS206
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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 (~155.11 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (7.76 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
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 (7.76 mM) in 10% DMSO + 90% Corn Oil (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 25.0 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 | 3.1021 mL | 15.5106 mL | 31.0212 mL | |
| 5 mM | 0.6204 mL | 3.1021 mL | 6.2042 mL | |
| 10 mM | 0.3102 mL | 1.5511 mL | 3.1021 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.
 Identification of Takinib as a potent and selective inhibitor of TAK1.Cell Chem Biol. 2017 Aug 17;24(8):1029-1039. |
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 Kinetic studies of the mode of inhibition of Takinib.Cell Chem Biol. 2017 Aug 17;24(8):1029-1039. |
 Takinib induces apoptosis in RA FLS and reduces IL-6 secretion.ARA FLS cells in the presence and absence of TNF were treated with titrations of Takinib and 5ZO for 48h.Cell Chem Biol. 2017 Aug 17;24(8):1029-1039. |
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