| Size | Price | Stock | Qty |
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| 5mg |
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| 10mg |
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| 25mg |
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| 50mg |
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| 100mg |
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| Targets |
MI-503 targets the menin-MLL interaction, a critical protein-protein interaction that drives leukemogenesis in MLL-rearranged leukemias. The compound inhibits the menin-MLL interaction with an IC₅₀ of 14.7 nM. By disrupting the binding of menin to MLL fusion proteins, MI-503 effectively inhibits downstream transcriptional programs associated with acute leukemia. MI-503 shows pronounced growth suppressive activity in a panel of human MLL leukemia cell lines with GI₅₀ values in the 250-570 nM range, but only a minimal effect in human leukemia cell lines without MLL translocations. The menin-MLL interaction is a critical driver of MLL-rearranged leukemias, and its inhibition represents a promising therapeutic strategy. MI-503'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 |
MI-503 forms hydrogen connections with Tyr276 by occupying the F9 and P13 pockets on menin. It also extends beyond the P13 pocket to make hydrogen bonds with Trp341 and Glu366. When MI-503 was applied to mouse bone marrow cells (BMC) that had been transformed with the mLL-AF9 oncogene, there was a noticeable growth inhibition (GI50 of 0.22 μM). After 7–10 days of treatment, MI–503 exhibits a considerable time-dependent cell growth inhibitory impact [1].
In vitro, MI-503 demonstrates potent inhibition of menin-MLL interaction and anti-leukemic activity. The compound inhibits the menin-MLL interaction with an IC₅₀ of 14.7 nM. MI-503 shows pronounced growth suppressive activity in a panel of human MLL leukemia cell lines with GI₅₀ values in the 250-570 nM range, but only a minimal effect in human leukemia cell lines without MLL translocations. In osteosarcoma studies, MI-503 dose-dependently suppressed cell proliferation in 6 OS cell lines, including 143B, HOS, Saos-2, SKES1, MG-63, and U2OS. The compound's effects on cell viability and proliferation can be assessed in various cancer cell lines. MI-503's high potency and selectivity make it a valuable tool for studying the role of menin-MLL signaling in cancer. The compound is soluble in DMSO, with a solubility of 88 mg/mL (155.85 mM). |
| ln Vivo |
After a single intravenous or oral dosage, MI-503 exhibits significant levels in peripheral blood and a high oral bioavailability of 75%. MI-503 administered intraperitoneally (ip) once day significantly reduces the growth of tumors. Two mice that received MI-503 treatment had total tumor regression and a reduction in MV4;11 tumor volume of more than 80%. Ten days of continuous MI-503 treatment greatly slowed the MLL leukemia progression in mice and greatly decreased the burden of leukemic tumors. The expression of Hoxa9 and Meis1, two downstream targets of MLL fusion proteins that are markedly elevated in MLL leukemia, was considerably reduced upon treatment with MI-503 and MI-463 [1].
In vivo, MI-503 demonstrates efficacy in various animal models of cancer. Immunohistochemistry studies showed that MI-503 suppressed H3K4 methylation and inhibited the expression of the cell proliferation biomarker Ki67 in 143B OS xenograft tissue. The compound demonstrated potent anti-OS activity in both in vitro and in vivo models, indicating that menin inhibitor may be a prospective therapeutic strategy for human osteosarcoma. In AML xenograft models, in vivo treatment with MI-503 significantly prolonged survival. For middle ear cholesteatoma studies, menin-MLL inhibitors were topically administered into a KGF-induced murine cholesteatoma for seven consecutive days. The compound's oral bioavailability and in vivo efficacy support its utility as a chemical probe for studying menin-MLL signaling. |
| Enzyme Assay |
In vitro binding assays for MI-503 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-503 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-503 is flowed over the chip at various concentrations. The binding affinity 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 |
Leukemia cells are treated with MI-503 or 0.25% DMSO and cultured
at 37 °C for 7 days. Media is changed at day 4, viable cell numbers are
restored to the original concentration and MI-503 are re-supplied. MTT
cell proliferation assay kit is then employed, and plates are read for
absorbance at 570 nm using a microplate reader[1].
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| Animal Protocol |
In vivo animal experiments for MI-503 employ various models of cancer. For osteosarcoma studies, immunodeficient mice are injected with 143B OS cells, and tumors are allowed to establish. MI-503 is administered orally or intraperitoneally at various doses and schedules. Tumor growth is measured using calipers, and tumor volume is calculated. Immunohistochemistry is used to assess H3K4 methylation and Ki67 expression in tumor tissue. For AML studies, xenograft models are used, and survival is monitored. For cholesteatoma studies, menin-MLL inhibitors are topically administered. The compound's effects on tumor growth and survival are assessed. Dosing regimens vary depending on the experimental objectives.
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| ADME/Pharmacokinetics |
The pharmacokinetic properties of MI-503 have been characterized in preclinical studies. The compound is orally bioavailable. MI-503 has a molecular weight of 564.63. The compound is soluble in DMSO, with a solubility of 88 mg/mL (155.85 mM). 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-503's pharmacokinetic profile supports its use as an in vivo research tool. However, detailed pharmacokinetic data for MI-503 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-503 has not been extensively characterized in the literature, as the compound is primarily used as a research tool. In cellular assays, MI-503 shows pronounced growth suppressive activity in MLL leukemia cell lines but only a minimal effect in human leukemia cell lines without MLL translocations. In animal studies, MI-503 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-503. 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-503 is a highly potent, selective, and orally bioavailable small molecule inhibitor of the menin-MLL interaction with an IC₅₀ of 14.7 nM. It shows pronounced growth suppressive activity in human MLL leukemia cell lines (GI₅₀ = 250-570 nM) but minimal effect in cell lines without MLL translocations. MI-503 has a molecular weight of 564.63. In vivo, MI-503 suppressed H3K4 methylation and inhibited Ki67 expression in 143B OS xenograft tissue. It demonstrated potent anti-OS activity in both in vitro and in vivo models. In AML xenograft models, MI-503 significantly prolonged survival. MI-503 is a research compound for studying epigenetic regulation in cancer, with no regulatory approval for clinical use.
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| Molecular Formula |
C28H27F3N8S
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|---|---|
| Molecular Weight |
564.6352
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| Exact Mass |
564.203
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| CAS # |
1857417-13-0
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| PubChem CID |
91667931
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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 |
782.9±60.0 °C at 760 mmHg
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| Flash Point |
427.3±32.9 °C
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| Vapour Pressure |
0.0±2.7 mmHg at 25°C
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| Index of Refraction |
1.712
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| LogP |
4.08
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
10
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
40
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| Complexity |
908
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CC1=C(C=CC2=C1C=C(N2CC3=CNN=C3)C#N)CN4CCC(CC4)NC5=C6C=C(SC6=NC=N5)CC(F)(F)F
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| InChi Key |
DETOMBLLEOZTMZ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C28H27F3N8S/c1-17-19(2-3-25-23(17)8-21(11-32)39(25)14-18-12-35-36-13-18)15-38-6-4-20(5-7-38)37-26-24-9-22(10-28(29,30)31)40-27(24)34-16-33-26/h2-3,8-9,12-13,16,20H,4-7,10,14-15H2,1H3,(H,35,36)(H,33,34,37)
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| Chemical Name |
4-Methyl-1-(1H-pyrazol-4-ylmethyl)-5-[[4-[[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino]-1-piperidinyl]methyl]-1H-indole-2-carbonitrile
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| Synonyms |
MI503 MI 503 MI-503
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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 : ~25 mg/mL (~44.28 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (3.68 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 20.8 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: ≥ 2.08 mg/mL (3.68 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 20.8 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 | 1.7710 mL | 8.8552 mL | 17.7104 mL | |
| 5 mM | 0.3542 mL | 1.7710 mL | 3.5421 mL | |
| 10 mM | 0.1771 mL | 0.8855 mL | 1.7710 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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