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Ml-265 (TEPP-46) is an effective activator of pyruvate kinase M2 (PKM2). ML265 induces the more active tetrameric state of PKM2 and the X-ray co-crystal structure shows that the activator binds at the dimer-dimer interface between two subunits of PKM2. TEPP-46 also induces a decrease in the intracellular levels of acetyl-coA, lactate, ribose phosphate and serine. TEPP-46 inhibits LPS-induced Hif-1α and IL-1β, as well as the expression of a range of other Hif-1α-dependent genes. TEPP-46 treatment significantly downregulates the expression of the M1 markers Il12p40 and Cxcl-10. Activation of PKM2 using TEPP-46 significantly inhibits FSL-1 and CpG-induced Il1b mRNA expression. TEPP-46 inhibits Mtb-induced Il1b mRNA levels, boosts Mtb-induced levels of Il10 mRNA, and has no effect on levels of Tnf.
In vivo, ML-265 (150 mg/kg) readily achieves maximal PKM2 activation measured in A549 xenograft tumors. ML265 was tested in a H1299 mouse xenograft model and showed significant reduction in tumor size, weight, and occurrence with no apparent toxicity over the 7-week experiment.
| Cell Experiment | |
|---|---|
| Cell lines | |
| Preparation method | |
| Concentrations | |
| Incubation time | |
| Animal Experiment | |
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| Animal models | U87 tumor cells were injected subcutaneously on the back of female BALB/c nude mice (aged 6 to 8 weeks) and grown to ~150 mm3 |
| Formulation | 40% (w/v) (2-hydroxypropyl)-b-cyclodextrin in water |
| Dosages | 50 mg/kg |
| Administration | intraperitoneal injection |
| Molecular Weight | 372.46 |
| Formula | C17H16N4O2S2 |
| CAS Number | 1221186-53-3 |
| Solubility (25°C) | DMSO 40 mg/mL |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
| Related Pyruvate Kinase Products |
|---|
| Sodium Monofluorophosphate
Monofluorophosphate is a competitive inhibitor of pyruvate kinase and alkaline phosphatase with Ki of 3.4 mM and 69 μM, respectively, which also irreversibly inhibits phosphorylase phosphatase with Ki of 0.5 mM. |
| PKM2-IN-1
PKM2-IN-1 (compound 3k) is a pyruvate kinase M2 (PKM2) inhibitor with an IC50 of 2.95 μM. The IC50 value for PKM1 is 4-5-fold higher than that for PKM2. |
| Mitapivat (AG-348)
Mitapivat (AG-348) is the first-in-class, oral effective pyruvate kinase small molecule allosteric activator. Mitapivat (AG-348) is active against wild-type and various mutated PKR enzymes, and promotes healthy red blood cell generation by activating mutated PKR to increase ATP levels. |
| DASA-58
DASA-58 is a potent activator of pyruvate kinase M2 (PKM2) with an AC90 of 680 nM, and an AC50 of 38 nM. |
| Etavopivat
Etavopivat, an oral erythrocyte pyruvate kinase activator, is being developed for sickle cell disease and other hemoglobinopathies, previously reported in 2019. |
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