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In vitro: MI-538 inhibits the proliferation of MLL leukemia cells with a GI50 of 83 nM. MI-538 shows no effect (up to 6 μM) on growth of the control cell lines HL-60 and HM-2, which do not harbor MLL translocations, demonstrating good selectivity toward MLL fusion protein transformed cells. MI-538 binds to menin with low nanomolar affinity (Kd=6.5 nM). Its potent cellular activity originates from the improved binding affinity to menin and possibly increased cell membrane permeability. Treatment with MI-538 results in strong down regulation of expression of Hoxa9 and Meis1 genes. About 100 nM 27 was sufficient to reduce by ~50% Hoxa9 expression in MLL-AF9 cells, and even more pronounced effect was seen on Meis1 expression. In vivo: Treatment with MI-538 results in a pronounced, about 80%, reduction in the MV4;11 tumor volume, without causing substantial signs of toxicity reflected by less than 10% reduction of the body weight. MI-538 demonstrates markedly improved exposure (area under the curve, AUC, values), Cmax (maximum compound concentration) in the blood plasma, and the lowest value of clearance. The half-life of MI-538 is about 1.6 h. MI-538 has also high oral bioavailability (~50%).
| Cell Experiment | |
|---|---|
| Cell lines | human MLL leukemia cell lines |
| Preparation method | We assessed the effect of this compound in human MLL leukemia cell lines, MV4;11 and MOLM13, harboring two different MLL translocations (MLL-AF4 and MLL-AF9, respectively) |
| Concentrations | 45 mg/kg |
| Incubation time | |
| Animal Experiment | |
|---|---|
| Animal models | C57BL/6 mice |
| Formulation | DMSO/PEG400/water (5:40:55, v/v/v) |
| Dosages | 15 mg/kg |
| Administration | i.v. |
| Molecular Weight | 566.6 |
| Formula | C27H25F3N8OS |
| CAS Number | 1857417-10-7 |
| Form | Solid |
| Solubility (25°C) | 10mM in DMSO |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
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