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| Targets |
VTP50469 targets the interaction between Menin (MEN1) and MLL1 (KMT2A). By inhibiting this protein-protein interaction, it reverses the leukemia gene expression driven by MLL fusion proteins. This leads to altered gene expression, differentiation, and apoptosis in leukemia cells. The compound's high selectivity and picomolar affinity make it a promising therapeutic strategy for MLL-rearranged AML.
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| ln Vitro |
Commercially available VTP50469 (MOLM13 (IC50: 13 nM), THP1 (IC50: 37 nM), NOMO1 (IC50: 30 nM), ML2 (IC50: 16 nM), EOL1 (IC50: 20 nM), and mouse MLL-AF9 cells (IC50 of 15 nM) and ALL (KOPN8 (IC50 of 15 nM), HB11;19 (IC50 of 36 nM), MV4;11 (IC50 of 17 nM), SEMK2 (IC50 of 27 nM), and RS4;11 (IC 50: 25 nM)) [1]. MLL-r B cells react dose-dependently to VTP50469 at early time points. VTP50469 is submitted by MLL-r AML cell lines 4-6 days following VTP50469. removed from the protein complex and stops MLL from labeling genes' chromatin. Changes in gene expression, yeast, and cell dormancy are caused by MLL-bound staining [1].
In vitro, VTP50469 is a highly potent inhibitor of the Menin-MLL interaction with a Ki of 104 pM. It selectively kills cell lines with MLL rearrangements and NPM1c+ mutations. The compound induces differentiation and apoptosis in leukemia cells, demonstrating its potential as an anti-leukemic agent. Its high selectivity ensures minimal effects on normal cells. |
| ln Vivo |
Treatment with VTP50469 (15-60 mg/kg; interventional; twice daily; 28 days; NSG mice) was highly successful at all dosages, with significant survival in all treatment groups. Advantages are 30 and 60 mg/kg
In vivo, VTP50469 exhibits potent anti-leukemic activity in mouse models. As an orally active compound, it can be administered to tumor-bearing mice to evaluate its efficacy. The compound has shown the ability to inhibit tumor growth and induce regression in MLL-rearranged leukemia models. Its oral bioavailability and potent activity make it a promising candidate for clinical development. |
| Enzyme Assay |
The in vitro binding assay for VTP50469 measures its affinity for the Menin protein. This is typically performed using surface plasmon resonance (SPR), isothermal titration calorimetry (ITC), or fluorescence polarization assays. The compound's ability to compete with a labeled Menin-binding peptide is measured, and the Ki value is calculated from dose-response curves. The Ki of 104 pM confirms its picomolar affinity.
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| Cell Assay |
In vitro cellular studies are conducted using leukemia cell lines with MLL rearrangements or NPM1c mutations. Cells are treated with VTP50469 at various concentrations. Cell viability is assessed using MTT or CellTiter-Glo assays. Differentiation is measured by assessing surface marker expression (e.g., CD11b, CD14) via flow cytometry. Apoptosis is evaluated by Annexin V/PI staining or caspase-3 activity assays. Gene expression changes are analyzed by qRT-PCR or RNA-seq.
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| Animal Protocol |
Animal/Disease Models: Unconditional Immunodeficient (NSG) mice with MV4;11 cells [1]
Doses: 15 mg/kg, 30 mg/kg and 60 mg/kg Route of Administration: Orally drug; twice (two times) daily; for 28 days Experimental Results: Highly effective at all dose levels, and all treatment groups had a significant survival advantage over the control group. In vivo animal experiments are performed using mouse xenograft models of MLL-rearranged AML. Tumor-bearing mice are administered VTP50469 via oral gavage at various doses. Tumor volume is measured over time, and endpoints include tumor growth inhibition, regression, and survival. Pharmacodynamic studies evaluate target engagement by measuring Menin-MLL complex disruption and downstream gene expression changes in tumor tissues. |
| ADME/Pharmacokinetics |
VTP50469 has a molecular formula of C34H42N8O4S and a molecular weight of 630.82 g/mol. It is soluble in DMSO (100 mg/mL) and ethanol (100 mg/mL) but insoluble in water. For storage, powder should be kept at -20°C. For in vivo administration, it can be formulated in appropriate vehicles such as CMC-Na or DMSO/PEG300/Tween 80/saline mixtures. The compound is supplied with high purity (>99%).
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| Toxicity/Toxicokinetics |
Toxicological data for VTP50469 are derived from preclinical studies. As a potent and selective inhibitor, it is for research use only and not intended for human therapeutic applications. No significant toxicity has been reported at effective doses in animal studies. Standard laboratory safety precautions should be followed when handling the compound due to its potent biological activity. Long-term toxicity and carcinogenicity studies are ongoing.
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| References |
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| Additional Infomation |
5-fluoro-2-({4-[7-({trans-4-[(methylsulfonyl)amino]cyclohexyl}methyl)-2,7-diazaspiro[3.5]nonan-2-yl]pyrimidin-5-yl}oxy)-N,N-di(propan-2-yl)benzamide is an organic molecular entity with antitumor activity.
VTP50469 is also known as VTP-50469. It is a novel, orally available Menin-MLL1 inhibitor being developed for the treatment of MLL-rearranged and NPM1c+ leukemias. The compound has been cited in high-impact journals including Cell and Nature Cell Biology. It represents a promising targeted therapy for genetically defined subsets of AML and is used in cancer research to study the role of the Menin-MLL interaction in leukemogenesis. |
| Molecular Formula |
C32H47FN6O4S
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|---|---|
| Molecular Weight |
630.8168
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| Exact Mass |
630.336
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| CAS # |
2169916-18-9
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| Related CAS # |
VTP50469 fumarate;2169919-29-1
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| PubChem CID |
132212900
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| Appearance |
White to light yellow solid powder
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| LogP |
4.4
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
10
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| Rotatable Bond Count |
10
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| Heavy Atom Count |
44
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| Complexity |
1040
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| Defined Atom Stereocenter Count |
0
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| SMILES |
S(C([H])([H])[H])(N([H])C1([H])C([H])([H])C([H])([H])C([H])(C([H])([H])C1([H])[H])C([H])([H])N1C([H])([H])C([H])([H])C2(C([H])([H])C1([H])[H])C([H])([H])N(C1C(=C([H])N=C([H])N=1)OC1C([H])=C([H])C(=C([H])C=1C(N(C([H])(C([H])([H])[H])C([H])([H])[H])C([H])(C([H])([H])[H])C([H])([H])[H])=O)F)C2([H])[H])(=O)=O
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| InChi Key |
ADHHOUXZPBYYSU-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C32H47FN6O4S/c1-22(2)39(23(3)4)31(40)27-16-25(33)8-11-28(27)43-29-17-34-21-35-30(29)38-19-32(20-38)12-14-37(15-13-32)18-24-6-9-26(10-7-24)36-44(5,41)42/h8,11,16-17,21-24,26,36H,6-7,9-10,12-15,18-20H2,1-5H3
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| Chemical Name |
5-fluoro-2-[4-[7-[[4-(methanesulfonamido)cyclohexyl]methyl]-2,7-diazaspiro[3.5]nonan-2-yl]pyrimidin-5-yl]oxy-N,N-di(propan-2-yl)benzamide
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| Synonyms |
VTP50469 VTP-50469
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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 : ~125 mg/mL (~198.15 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (3.96 mM) (saturation unknown) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (3.96 mM) (saturation unknown) in 5% DMSO + 95% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (3.30 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. Solubility in Formulation 4: ≥ 2.08 mg/mL (3.30 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 5: ≥ 2.08 mg/mL (3.30 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. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.5852 mL | 7.9262 mL | 15.8524 mL | |
| 5 mM | 0.3170 mL | 1.5852 mL | 3.1705 mL | |
| 10 mM | 0.1585 mL | 0.7926 mL | 1.5852 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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