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| Targets |
MI-2-2 targets menin, a scaffold protein that interacts with MLL (mixed-lineage leukemia) fusion proteins. The compound binds to menin with low nanomolar affinity (Kd = 22 nM). MI-2-2 inhibits the menin-MLL interaction with an IC₅₀ of 46 nM. By disrupting the menin-MLL interaction, MI-2-2 inhibits downstream transcriptional programs associated with acute leukemia. The compound shows specific and highly significant activity in MLL leukemia cells, including inhibition of cell growth/proliferation, downregulation of Hoxa9 expression, and differentiation. The menin-MLL interaction is a critical driver of MLL-rearranged leukemias, and its inhibition represents a promising therapeutic strategy. MI-2-2's high affinity and selectivity for menin make it a valuable tool for studying the role of menin-MLL signaling in cancer.
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| ln Vitro |
Menin's interaction with MBM1 (IC50= 46 nM) and the bivalent MLL fragment that contains MBM1 and MBM2 (IC50= 520 nM) is inhibited by MI-2-2. When BMC, a human leukemia cell line with the MLL-AF4 translocation, is transformed with MLL-AF9 and MV4;11, MI-2-2 shows highly significant activity at low micromolar doses [1].
In vitro, MI-2-2 demonstrates potent inhibition of menin-MLL interaction and anti-leukemic activity. The compound binds to menin with a Kd of 22 nM and inhibits the menin-MLL interaction with an IC₅₀ of 46 nM. Menin's interaction with MEM1 (IC₅₀ = 46 nM) and the bivalent MLL fragment that contains MEM1 and MEM2 (IC₅₀ = 520 nM) is inhibited by MI-2-2. When BMC, a human leukemia cell line with the MLL-AF4 translocation, is transformed with MLL-AF9 and MV4;11, MI-2-2 shows highly significant activity at low micromolar doses. MI-2-2 shows specific and highly significant activity in MLL leukemia cells, including inhibition of cell growth/proliferation, downregulation of Hoxa9 expression, and differentiation. The compound's effects on cell viability and proliferation can be assessed in various MLL-rearranged leukemia cell lines. MI-2-2 is additive with doxorubicin, with 100 nM doxorubicin and 30 μM MI-2-2 leading to the lowest cell numbers and inducing the most apoptosis. |
| ln Vivo |
In vivo, MI-2-2 has been evaluated in animal models of MLL-rearranged leukemia. The compound demonstrates efficacy in inhibiting tumor growth and prolonging survival. MI-2-2 is additive with doxorubicin in vivo, suggesting potential for combination therapy. The compound's in vivo efficacy supports the therapeutic potential of menin-MLL inhibition in MLL-rearranged leukemias. MI-2-2 is a second-generation inhibitor that exhibits strongly enhanced cellular activities compared with earlier compounds. The compound's oral bioavailability and pharmacokinetic properties have been characterized in preclinical studies. However, detailed in vivo study data for MI-2-2 is limited in the available literature, as the compound is primarily a research tool. The compound's efficacy in mouse models of MLL leukemia has been demonstrated, supporting its utility as a chemical probe.
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| Enzyme Assay |
In vitro binding assays for MI-2-2 employ fluorescence polarization or surface plasmon resonance to measure the inhibition of menin-MLL interaction. For fluorescence polarization assays, menin protein is incubated with a fluorescently labeled MLL peptide in the presence or absence of MI-2-2 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-2-2 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-2-2 typically employ MLL-rearranged leukemia cell lines, such as MV4;11, or BMC cells transformed with MLL-AF9. Cells are cultured in appropriate media and treated with MI-2-2 at various concentrations. Cell proliferation is assessed using standard assays such as MTT, resazurin reduction, or cell counting. Hoxa9 expression is measured by qPCR or Western blotting to assess the compound's effects on downstream targets. Cell differentiation is assessed by measuring surface markers or morphological changes. For studies investigating combination therapy, cells are treated with MI-2-2 and other agents such as doxorubicin, and cell viability and apoptosis are assessed. The compound's effects on signaling pathways can be assessed by Western blotting or other methods.
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| Animal Protocol |
In vivo animal experiments for MI-2-2 employ mouse xenograft models of MLL-rearranged leukemia. Immunodeficient mice are injected with MLL-rearranged leukemia cells, and tumors are allowed to establish. MI-2-2 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. For combination studies, MI-2-2 is administered with doxorubicin or other agents. 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-2-2 have been characterized in preclinical studies. The compound has a molecular weight of 415.50 and a molecular formula of C₁₇H₂₀F₃N₅S₂. MI-2-2 is a small molecule with properties suitable for oral administration. 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-2-2 is a second-generation inhibitor with improved properties compared with earlier compounds. The compound's pharmacokinetic profile supports its use as an in vivo research tool. However, detailed pharmacokinetic data for MI-2-2 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-2-2 has not been extensively characterized in the literature, as the compound is primarily used as a research tool. In cellular assays, MI-2-2 shows specific activity in MLL leukemia cells with minimal effect in human leukemia cell lines without MLL translocations. In animal studies, MI-2-2 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-2-2. 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-2-2 is a potent, selective small-molecule inhibitor of menin that binds with a Kd of 22 nM and inhibits the menin-MLL interaction with an IC₅₀ of 46 nM. It shows specific and highly significant activity in MLL leukemia cells, including inhibition of cell growth/proliferation, downregulation of Hoxa9 expression, and differentiation. MI-2-2 is additive with doxorubicin, with 100 nM doxorubicin and 30 μM MI-2-2 leading to the lowest cell numbers and inducing the most apoptosis. The compound has a molecular weight of 415.50 and a molecular formula of C₁₇H₂₀F₃N₅S₂. MI-2-2 is a second-generation inhibitor that exhibits strongly enhanced cellular activities compared with earlier compounds. It is a research tool for studying epigenetic regulation in cancer, particularly MLL-rearranged leukemias, with no regulatory approval for clinical use.
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| Molecular Formula |
C17H20F3N5S2
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|---|---|
| Molecular Weight |
415.4972
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| Exact Mass |
415.111
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| CAS # |
1454920-20-7
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| PubChem CID |
72201086
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| Appearance |
White to off-white solid powder
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| Density |
1.5±0.1 g/cm3
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| Boiling Point |
515.1±60.0 °C at 760 mmHg
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| Flash Point |
265.3±32.9 °C
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| Vapour Pressure |
0.0±1.3 mmHg at 25°C
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| Index of Refraction |
1.680
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| LogP |
2.22
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
27
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| Complexity |
577
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
SFDROHXKTATJBI-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C17H20F3N5S2/c1-16(2)9-21-15(27-16)25-5-3-24(4-6-25)13-12-7-11(8-17(18,19)20)26-14(12)23-10-22-13/h7,10H,3-6,8-9H2,1-2H3
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| Chemical Name |
4-[4-(5,5-dimethyl-4H-1,3-thiazol-2-yl)piperazin-1-yl]-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidine
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| Synonyms |
MI 2 2; MI22; MI-2-2
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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 Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light. |
| 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 (~240.67 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 3.75 mg/mL (9.03 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 37.5 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4067 mL | 12.0337 mL | 24.0674 mL | |
| 5 mM | 0.4813 mL | 2.4067 mL | 4.8135 mL | |
| 10 mM | 0.2407 mL | 1.2034 mL | 2.4067 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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