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| Targets |
MI-3454 targets the menin-MLL1 protein-protein interaction. Menin is a scaffold protein that interacts with MLL1 (mixed lineage leukemia 1) to regulate the expression of key genes involved in leukemogenesis, including HOXA9 and MEIS1. By inhibiting this interaction with an IC50 of 0.51 nM, MI-3454 disrupts the transcriptional program driven by MLL1 fusion proteins.
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| ln Vitro |
The proliferation of myeloid cells transformed with MLL-AF9 or Hoxa9/Meis1 is significantly inhibited by MI-3454 (0.001-10 μM; 7 days) [1]. In the human blood cell line, MI-3454 (50 nM; 6 days) induces MV-MI-3454 fusion, which dramatically lowers the viability of several leukocytes carrying MLL proteins (MLL-AF9, MLL-AF4, MLL-ENL), GI50 range Expression levels of HOXA9 and MEIS1 in 4-11 cells or MOLM13 [1]. ranges between 7 and 27 nM. Foamy menin is bound by MI-3454 to a segment of MLL14–43 that contains the complete menin binding motif [1]. Cytochrome P450 is not efficiently inhibited by MI-3454 (less than 50% inhibition at 10 μM) [1]. Assay for proliferation [1]
In vitro, MI-3454 (0.001-10 µM; 7 days) strongly reduces the proliferation of murine bone marrow cells transformed with MLL-AF9 or Hoxa9/Meis1. It markedly reduces the viability of leukemic cells harboring various MLL fusion proteins (MLL-AF9, MLL-AF4, MLL-ENL) with GI50 values ranging from 7 to 27 nM. MI-3454 (50 nM; 6 days) leads to downregulated expression of HOXA9 and MEIS1 in human leukemic cell lines MV-4-11 and MOLM13. |
| ln Vivo |
MI-3454 causes full leukemia or regression in mixed lineage leukemia 1 (MLL1) rearranged or nucleophosmin 1 (NPM1) variant leukemia models [1]. MI-3454 (120 mg/kg orally; once or twice daily for 7 days) potently halts leukemia progression with once-day dosing [1]. MI-3454 (100 mg/kg sidewall; bid; for 19 days) is effective in leukemia progression throughout treatment and considerably prolongs MOLM13 xenograft MI-3454 causes full remission in a patient-derived xenograft (PDX) model of MLL leukemia or inhibit the progression of leukemia [1]. MI-3454 (100 mg/kg IV or 15 mg/kg IV) has a T1/2 of 3.2 hours and an interface Cmax of 4698 mg/mL [1]. MI-3454 showed good stability in mouse and human liver microsomes (t = 20.4 minutes and 37.1, respectively). MI-3454 has low levels in the brain and CSF fluid, showing its potential to pass the blood-brain barrier. Limited [1].
In vivo, MI-3454 induces complete remission or regression of leukemia in mouse models of MLL1-rearranged or NPM1-mutated leukemia through downregulation of key genes involved in leukemogenesis. The compound is orally bioactive and has shown potent anti-leukemic activity in preclinical models. Specific dosing regimens and efficacy data are detailed in the primary research literature. |
| Enzyme Assay |
The in vitro enzyme assay for MI-3454 involves measuring the inhibition of the menin-MLL1 interaction. A fluorescence polarization or AlphaScreen assay is typically used, where a fluorescently labeled MLL peptide (e.g., MLL14-43 fragment) competes with the compound for binding to menin protein. The IC50 value of 0.51 nM is determined by fitting dose-response curves.
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| Cell Assay |
Proliferation assay[1]
Cell Types: Mouse bone marrow cells transformed with MLL-AF9 or Hoxa9/Meis1 Tested Concentrations: 0.001, 0.01, 0.1, 1, 10 μM Incubation Duration: 7 days Experimental Results: demonstrated a strong reduction in cell proliferation. RT-PCR[1] Cell Types: Human leukemia cell line MV-4-11 cells or MOLM13 Tested Concentrations: 50 nM Incubation Duration: 6 days Experimental Results: Resulting in down-regulation of the expression of HOXA9 and MEIS1 and the expression levels of other MLL fusion target genes, including MEF2C, DLX2, HOXA10, PBX3 and FLT3. Cellular assays are performed using human leukemic cell lines (MV-4-11, MOLM13) or murine bone marrow cells transformed with MLL fusion proteins. Cells are treated with MI-3454 at concentrations ranging from 0.001-10 µM for 6-7 days. Cell viability is assessed using CellTiter-Glo or MTT assays. Gene expression changes (HOXA9, MEIS1) are measured by RT-qPCR. |
| Animal Protocol |
Animal/Disease Models: 8 to 10 weeks old female NSG mice (MV-4 minutes) [1]. -11 MLL leukemia xenograft model) [1]
Doses: 120 mg/kg Route of Administration: oral; Once or twice (two times) daily for 7 days Experimental Results: Once-daily treatment was enough to halt the progression of leukemia. Animal/Disease Models: Female CD-1 mice [1] Doses: 100 mg/kg (PO) or 15 mg/kg (IV) (pharmacokinetic/PK/PK analysis) Route of Administration: PO or IV Experimental Results:T1/2 is 3.2 hrs (hrs (hours)), Cmax PO is 4698 mg/mL. The T1/2 of IV was 2.4 hrs (hrs (hours)), the CL was 2375 mL/hour·kg, and the Vss was 5358 mL/kg. In vivo animal studies are conducted in mouse models of MLL1-rearranged or NPM1-mutated leukemia. MI-3454 is administered orally. Tumor burden is monitored by bioluminescence imaging or flow cytometry, and survival is recorded. The compound induces complete remission or regression of leukemia in these models. |
| ADME/Pharmacokinetics |
MI-3454 is an orally active compound with favorable pharmacokinetic properties. It is a highly potent inhibitor with an IC50 of 0.51 nM. The compound is absorbed after oral administration and achieves sufficient systemic exposure to exert anti-leukemic activity in mouse models. Specific PK parameters such as half-life, Cmax, and AUC are available in the primary research literature.
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| Toxicity/Toxicokinetics |
Toxicity data for MI-3454 are not extensively detailed in the available sources. As an investigational compound, it has been evaluated in preclinical models, but specific toxicological profiles are not provided in the supplier documentation. The compound is intended for research use only and not for human therapeutic use.
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| References | |
| Additional Infomation |
MI-3454 is a research compound being investigated for the treatment of acute leukemias with MLL1 translocations or NPM1 mutations. It is a second-generation menin-MLL1 inhibitor with significantly improved potency over earlier compounds. The compound is available from commercial suppliers for research use only. A reference publication describing its discovery and characterization is available in the primary literature.
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| Molecular Formula |
C32H35F3N8OS
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| Molecular Weight |
636.7335
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| Exact Mass |
636.26
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| CAS # |
2134169-43-8
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| Related CAS # |
2134169-43-8;MI-3454 HCl;
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| PubChem CID |
130443890
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| Appearance |
Light brown to brown solid powder
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| LogP |
6.1
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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 |
9
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| Heavy Atom Count |
45
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| Complexity |
1120
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| Defined Atom Stereocenter Count |
0
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| SMILES |
S1C(C([H])([H])C(F)(F)F)=C([H])C2C1=NC(N([H])C([H])([H])[H])=NC=2N([H])C1([H])C([H])([H])C([H])([H])N(C([H])([H])C1([H])[H])C([H])([H])C1C([H])=C([H])C2=C(C=1C([H])([H])[H])C([H])=C(C#N)N2C([H])([H])C12C([H])([H])C(C1([H])[H])(C2([H])[H])N([H])C([H])=O
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| InChi Key |
MBFYNGBMAACLAT-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C32H35F3N8OS/c1-19-20(3-4-26-24(19)9-22(12-36)43(26)17-30-14-31(15-30,16-30)38-18-44)13-42-7-5-21(6-8-42)39-27-25-10-23(11-32(33,34)35)45-28(25)41-29(37-2)40-27/h3-4,9-10,18,21H,5-8,11,13-17H2,1-2H3,(H,38,44)(H2,37,39,40,41)
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| Chemical Name |
N-[3-[[2-cyano-4-methyl-5-[[4-[[2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino]piperidin-1-yl]methyl]indol-1-yl]methyl]-1-bicyclo[1.1.1]pentanyl]formamide
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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. |
| 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 : ~31.25 mg/mL (~49.08 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: 5 mg/mL (7.85 mM) in 20% HP-β-CD 5% Cremophor EL (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
(Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.5705 mL | 7.8526 mL | 15.7052 mL | |
| 5 mM | 0.3141 mL | 1.5705 mL | 3.1410 mL | |
| 10 mM | 0.1571 mL | 0.7853 mL | 1.5705 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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