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Purity: ≥98%
TEPP-46 (CID-44246499; NCGC-00186528; ML265) is a novel potent and selective small molecule activator of pyruvate kinase M2 (PKM2) with antitumor activity. It activates PKM2 with an EC50 of 92 nM, and shows little or no effect on PKM1, PKL and PKR. Macrophages activated by the TLR4 agonist LPS undergo dramatic changes in their metabolic activity. LPS induces expression of the key metabolic regulator Pyruvate Kinase M2 (PKM2). Activation of PKM2 using the well-characterized small molecules, TEPP-46, inhibited LPS-induced Hif-1α and IL-1β, as well as the expression of a range of other Hif-1α-dependent genes. Activation of PKM2 attenuated an LPS-induced proinflammatory M1 macrophage phenotype while promoting traits typical of an M2 macrophage. LPS-induced PKM2 enters into a complex with Hif-1α, which can directly bind to the IL-1β promoter, an event that is inhibited by activation of PKM2. TEPP-46 inhibited LPS-induced glycolytic reprogramming and succinate production. Finally, activation of PKM2 by TEPP-46 in vivo inhibited LPS and Salmonella typhimurium-induced IL-1β production, while boosting production of IL-10. PKM2 is therefore a critical determinant of macrophage activation by LPS, promoting the inflammatory response.
| ln Vitro |
Through a mechanism like that of the endogenous activator FBP, TEPP-46 and DASA-58 activate PKM2. Pre-treating cells with DASA-58 or TEPP-46 inhibits the suppression of PKM2 activity caused by pervanadate. Moreover, acetyl-coA, lactate, ribose phosphate, and serine intracellular levels are decreased by TEPP-46[1]. TEPP-46 suppresses the expression of several other Hif-1α-dependent genes as well as IL-1β and Hif-1α that are stimulated by LPS. Treatment with TEPP-46 dramatically reduces the expression of Cxcl-10 and Il12p40, two M1 indicators. PKM2 activation with TEPP-46 dramatically reduces the expression of Il1b mRNA produced by CpG and FSL-1. TEPP-46 has no effect on Tnf levels but increases Mtb-induced levels of Il10 mRNA and suppresses Mtb-induced levels of Il1b mRNA[2].
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| ln Vivo |
With a lengthy half-life, low clearance, and a good volume of distribution, TEPP-46 demonstrates strong oral bioavailability and exhibits metrics that indicate drug exposure in tumor tissues. In A549 xenograft tumors, TEPP-46 at 150 mg/kg easily reaches maximal PKM2 activation[1].
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| References |
[1]. Anastasiou D, et al. Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis. Nat Chem Biol. 2012 Oct;8(10):839-847.
[2]. Palsson-McDermott EM, et al. Pyruvate kinase M2 regulates Hif-1α activity and IL-1β induction and is a critical determinant of the warburg effect in LPS-activated macrophages. Cell Metab. 2015 Jan 6;21(1):65-80 |
| Molecular Formula |
C17H16N4O2S2
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| Molecular Weight |
372.46
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| CAS # |
1221186-53-3
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| SMILES |
O=C1C(N(C)C2=C3SC(S(C)=O)=C2)=C3C=NN1CC4=CC=CC(N)=C4
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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: ≥ 2.87 mg/mL (7.71 mM) (saturation unknown) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
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 (6.71 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. View More
Solubility in Formulation 3: 2.5 mg/mL (6.71 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. Solubility in Formulation 4: ≥ 2.08 mg/mL (5.58 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 corn oil and mix evenly. Solubility in Formulation 5: 10 mg/mL (26.85 mM) in 50% PEG300 50% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 6: 5 mg/mL (13.42 mM) in 0.5% CMC-Na/saline water (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.6849 mL | 13.4243 mL | 26.8485 mL | |
| 5 mM | 0.5370 mL | 2.6849 mL | 5.3697 mL | |
| 10 mM | 0.2685 mL | 1.3424 mL | 2.6849 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.
Activation of PKM2 using TEPP-46 attenuates the M1 attributes of LPS-activated BMDMs.Cell Metab.2015 Jan 6;21(1):65-80. |
Activation of PKM2 counteracts LPS induced excessive rate of glycolysis and restores cellular levels of succinate.Cell Metab.2015 Jan 6;21(1):65-80. |
Activation of PKM2in vivodiminishes the host immune response in LPS-induced sepsis and in anS. typhimuriummodel of infection.Cell Metab.2015 Jan 6;21(1):65-80. |
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