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 | |
|---|---|
| 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 |
| Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
| Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
| Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
| Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
| Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
| Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
| Related Pyruvate Kinase Products |
|---|
| ZY-1
ZY-1 is a control molecule of ZY-2. |
| PKR activator 4
PKR activator 4 is a potent pyruvate kinase R (PKR) activator. |
| CIAC001
CIAC001 is a Pyruvate Kinase PKM2 inhibitor with anti-neuroinflammatory activity. |
| PKM2/PDK1-IN-1
PKM2/PDK1-IN-1, one of shikonin thioether derivatives, is a dual inhibitor of PKM2/PDK1. |
| PKM2-IN-4
Pkm2-in-4 is a selective inhibitor of PKM2 (IC50=0.35 μM), which regulates pyruvate-dependent respiration and induces mitochondrial H202 production rate and electron transport system coupling. |
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