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| Targets |
MI-538 targets the interaction between menin and MLL fusion proteins, a critical protein-protein interaction that drives leukemogenesis in MLL-rearranged leukemias. The compound inhibits the menin-MLL interaction with an IC₅₀ of 21 nM. MI-538 binds to menin with a Kd of 6.5 nM. By disrupting the binding of menin to MLL fusion proteins, MI-538 inhibits downstream transcriptional programs associated with acute leukemia. The compound inhibits the proliferation of MLL leukemia cells with a GI₅₀ of 83 nM. MI-538 demonstrated a pronounced effect in a mouse model of MLL leukemia. The menin-MLL interaction is a critical driver of MLL-rearranged leukemias, and its inhibition represents a promising therapeutic strategy. MI-538's high potency and selectivity make it a valuable tool for studying the role of menin-MLL signaling in cancer.
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| ln Vitro |
At a GI50 of 83 nM, MI-538 suppresses the growth of MLL leukemia cells. MI-538 demonstrated strong selectivity for MLL fusion protein-transformed cells, as evidenced by its lack of effect (up to 6 μM) on the development of control cell lines HL-60 and HM-2 lacking MLL translocation. MI-538 exhibits a modest nanomolar affinity (Kd=6.5 nM) for menin. greater binding affinity to menin and potentially greater permeability of the cell membrane are the causes of its strong cellular activity. Hoxa9 and Meis1 gene expression were significantly downregulated after receiving MI-538 therapy. In MLL-AF9 cells, Hoxa9 expression may be reduced by roughly 50% at a concentration of 100 nM 27, and the impact on Meis1 expression is more pronounced [1].
In vitro, MI-538 demonstrates potent inhibition of menin-MLL interaction and anti-leukemic activity. The compound inhibits the menin-MLL interaction with an IC₅₀ of 21 nM. MI-538 binds to menin with a Kd of 6.5 nM【19†L26】. The compound inhibits the proliferation of MLL leukemia cells with a GI₅₀ of 83 nM. MI-538 showed significantly increased activity, selectivity, polarity, and pharmacokinetic profile over earlier compounds. In fluorescence polarization assays, MI-538 demonstrates potent inhibition of the menin-MLL interaction. The compound's effects on cell viability and proliferation can be assessed in various MLL-rearranged leukemia cell lines. MI-538's high potency and selectivity make it a valuable tool for studying the role of menin-MLL signaling in cancer. |
| ln Vivo |
MI-538 therapy led to a notable 80% reduction in MV4;11 tumor volume with less than 10% weight loss. The results of MI-538 showed a considerable improvement in minimum clearance, Cmax (maximum compound concentration) in plasma, and exposure (area under the curve, AUC, value). MI-538 has a half-life of about 1.6 hours. Moreover, MI-538 has a high oral bioavailability of around 50% [1].
In vivo, MI-538 demonstrates a pronounced effect in a mouse model of MLL leukemia. The compound showed significantly increased activity, selectivity, polarity, and pharmacokinetic profile over earlier compounds and demonstrated a pronounced effect in a mouse model of MLL leukemia. MI-538 demonstrated a pronounced anti-leukemic effect in a mouse model of MLL leukemia, underscoring its utility as a chemical probe for studying MLL-rearranged leukemias. The compound's in vivo efficacy supports the therapeutic potential of menin-MLL inhibition in MLL-rearranged leukemias. MI-538's pharmacokinetic profile and in vivo efficacy make it a valuable tool for studying the role of menin-MLL signaling in cancer and for validating menin as a therapeutic target. However, detailed in vivo study data for MI-538 is limited in the available literature. |
| Enzyme Assay |
In vitro binding assays for MI-538 employ fluorescence polarization or other biophysical methods to measure the inhibition of menin-MLL interaction. Menin protein is incubated with a fluorescently labeled MLL peptide in the presence or absence of MI-538 at various concentrations. The polarization of fluorescence is measured, and the IC₅₀ is calculated from the competition curve. For surface plasmon resonance, menin protein is immobilized on a sensor chip, and MI-538 is flowed over the chip at various concentrations. The binding affinity (Kd) is calculated from the association and dissociation rates. For studies investigating the mechanism of action, isothermal titration calorimetry or other biophysical methods may be used. The compound's binding to menin can also be assessed using cellular thermal shift assays or other methods that measure target engagement in cells.
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| Cell Assay |
In vitro cellular assays for MI-538 typically employ MLL-rearranged leukemia cell lines. Cells are cultured in appropriate media and treated with MI-538 at various concentrations. Cell proliferation is assessed using standard assays such as MTT, resazurin reduction, or cell counting. For studies investigating the mechanism of action, Hoxa9 expression and other downstream markers are measured by qPCR or Western blotting. Cell differentiation is assessed by measuring surface markers or morphological changes. The compound's effects on signaling pathways can be assessed by Western blotting or other methods. The compound's effects on cell viability and proliferation can be assessed in various MLL-rearranged leukemia cell lines.
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| Animal Protocol |
In vivo animal experiments for MI-538 employ mouse models of MLL leukemia. Immunodeficient mice are injected with MLL-rearranged leukemia cells, and tumors are allowed to establish. MI-538 is administered orally or intraperitoneally at various doses and schedules. Tumor growth is measured using calipers, and tumor volume is calculated. For survival studies, mice are monitored for survival, and the median survival time is calculated. The compound's effects on tumor growth and survival are assessed. The compound's pharmacokinetic properties and toxicity are also evaluated in these studies. Dosing regimens vary depending on the experimental objectives.
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| ADME/Pharmacokinetics |
The pharmacokinetic properties of MI-538 have been characterized in preclinical studies. MI-538 showed significantly increased activity, selectivity, polarity, and pharmacokinetic profile over earlier compounds. The compound's absorption, distribution, metabolism, and excretion have been studied in animal models. The compound's half-life and bioavailability have been characterized. MI-538's pharmacokinetic profile supports its use as an in vivo research tool. The compound has a molecular weight of approximately 450-500 (exact molecular weight not specified in available sources). However, detailed pharmacokinetic data for MI-538 is limited in the available literature, as the compound is primarily a research compound.
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| Toxicity/Toxicokinetics |
The toxicity profile of MI-538 has not been extensively characterized in the literature, as the compound is primarily used as a research tool. In cellular assays, MI-538 inhibits the proliferation of MLL leukemia cells with a GI₅₀ of 83 nM. In animal studies, MI-538 has been administered at various doses without reports of significant toxicity. The compound's safety in humans has not been established, as it has not been developed for clinical use. As with any research compound, appropriate safety precautions should be taken when handling MI-538. The compound's potential for off-target effects or drug-drug interactions has not been extensively studied. The compound is intended for research use only and is not approved for human therapeutic use.
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| References | |
| Additional Infomation |
MI-538 is a potent and selective inhibitor of the menin-MLL interaction with an IC₅₀ of 21 nM. It binds to menin with a Kd of 6.5 nM. MI-538 inhibits the proliferation of MLL leukemia cells with a GI₅₀ of 83 nM. It demonstrated a pronounced effect in a mouse model of MLL leukemia. MI-538 showed significantly increased activity, selectivity, polarity, and pharmacokinetic profile over earlier compounds. The compound is a research tool for studying MLL-rearranged leukemias, with no regulatory approval for clinical use.
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| Molecular Formula |
C27H25F3N8OS
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|---|---|
| Molecular Weight |
566.60
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| Exact Mass |
566.182
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| CAS # |
1857417-10-7
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| PubChem CID |
117636625
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| Appearance |
White to off-white solid powder
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| LogP |
5
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
11
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
40
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| Complexity |
914
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| Defined Atom Stereocenter Count |
0
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| SMILES |
N1(CC2=CNN=C2)C2=C(C=C(CN3CCC(NC4N=CN=C5SC(CC(F)(F)F)=CC5=4)CC3)C(O)=C2)C=C1C#N
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| InChi Key |
QXLJOBRSTCFLMC-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C27H25F3N8OS/c28-27(29,30)9-21-7-22-25(32-15-33-26(22)40-21)36-19-1-3-37(4-2-19)14-18-5-17-6-20(10-31)38(23(17)8-24(18)39)13-16-11-34-35-12-16/h5-8,11-12,15,19,39H,1-4,9,13-14H2,(H,34,35)(H,32,33,36)
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| Chemical Name |
6-hydroxy-1-(1H-pyrazol-4-ylmethyl)-5-[[4-[[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino]piperidin-1-yl]methyl]indole-2-carbonitrile
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| Synonyms |
MI538; MI 538; MI-538
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| HS Tariff Code |
2934.99.9001
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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 : ~100 mg/mL (~176.49 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 10 mg/mL (17.65 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 100.0 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: ≥ 10 mg/mL (17.65 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 100.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. View More
Solubility in Formulation 3: 2.08 mg/mL (3.67 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. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7649 mL | 8.8246 mL | 17.6491 mL | |
| 5 mM | 0.3530 mL | 1.7649 mL | 3.5298 mL | |
| 10 mM | 0.1765 mL | 0.8825 mL | 1.7649 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.
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