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| 5mg |
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VU661013 is a novel and potent MCL-1 Inhibitor combining with Venetoclax for rescuing Venetoclax Resistant Acute Myelogenous Leukemia. VU661013 is a potent, selective MCL-1 inhibitor that destabilizes the BIM/MCL-1 association, induces apoptosis in AML, and is effective in cells that are resistant to venetoclax and patient-derived xenografts. Venetoclax was also safely combined with VU661013 for synergy in murine models of AML.
| Targets |
Mcl-1 (Ki = 97 pM)
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|---|---|
| ln Vitro |
In a TR-FRET assay, VU661013 displaces a fluorescently labeled peptide derived from the pro-apoptotic protein BAK, exhibiting a Ki of 97±30 pM to human MCL-1. VU661013 does not significantly inhibit BCL-xL (Ki>40 μM) or BCL-2 (Ki=0.73 μM)[1].
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| ln Vivo |
In AML, VU661013 destabilizes the BIM/MCL-1 association, induces apoptosis, and is effective in Venetoclax-resistant cells and patient-derived xenografts. After developing disseminated leukemia, NSGS mice receive intraperitoneal doses of 10, 25, or 75 mg/kg of VU661013 every day for 21 days. Using anti-human CD45 (hCD45) and anti-hCD33 monoclonal antibodies, weekly chimerism analyses are carried out and the percentage of MV-4-11 cells in murine peripheral blood is measured. Vehicle-treated mice have developed significant leukemia burdens 28 days after transplant, so they are sacrificed and their organs are collected for examination. Vehicle-treated mice died from xenografted AML, but there was no sign of VU661013-related toxicity in any organs other than the target organs. Disseminated human AML patients treated with VU661013 experience a dose-dependent reduction in tumor burden, nearly eliminating the hCD45+ MV-4-11 cells at the 75 mg/kg dose in the blood (mean, 13.0±2.2% in vehicle vs 7.4±7.2% in 25mg/kg vs 0.17±0.12% in 75 mg/kg treated mice), bone marrow (mean, 40.7±13.9% in vehicle vs 33.46±4.0 % in 25 mg/kg vs 0.384±0.345 in 75 mg/kg treated mice), and spleen (mean, 46.22±13.3% in vehicle vs 13.31±10.0% in 25 mg/kg vs 1.588±1.51% in 75 mg/kg treated mice). Treatment with VU661013 lowers the average amount of splenomegaly associated with the disease (mean, vehicle vs. 75mg/kg, 0.17±0.02 vs 0.09±0.01g), and amendeding spleen to body weight ratio (vehicle vs 75mg/kg, 0.99 vs 0.50). Mice are monitored in a second MV-4-11 xenograft study until they die, and Kaplan-Meier analysis is used to gauge survival. In this study, NSGS mice are given daily treatments of either vehicle alone, 15 mg/kg of VU661013, or 75 mg/kg of VU661013, starting seven days after transplant. Analysis reveals an increase in survival in mice treated with the 75mg/kg dose (vehicle treated mice=31 days, vs 15 mg/kg=32 days, vs 75 mg/kg treated mice=43 Days)[1].
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| Cell Assay |
The treatment of MV-4-11 cells with VEN (5 nM to 2.5 μM) or VU661013 (100 nM to 5 μM) at progressively higher concentrations over a period of three months results in cells that are resistant to BCL-2 or MCL-1 inhibition. When cells can sustain 100% viability in the presence of these potent inhibitor concentrations (5 μM for VU661013 and 2.5 μM for VEN), they are said to be VEN or VU661013-resistant[1].
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| References |
| Molecular Formula |
C39H39CL2N5O4
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|---|---|
| Molecular Weight |
712.66406750679
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| Exact Mass |
711.24
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| Elemental Analysis |
C, 65.73; H, 5.52; Cl, 9.95; N, 9.83; O, 8.98
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| CAS # |
2131184-57-9
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| Related CAS # |
2131184-57-9
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| PubChem CID |
134828256
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
8.1
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
50
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| Complexity |
1230
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| Defined Atom Stereocenter Count |
1
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| SMILES |
C[C@@H]1CN(C(=O)C2=C(C3=C(N12)C(=C(C=C3)Cl)C4=C(N(N=C4C)C)C)CCCOC5=CC(=C(C(=C5)C)Cl)C)C6=CN(C7=C6C=C(C=C7)C(=O)O)C
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| InChi Key |
BSAYHBZFNXDOIJ-JOCHJYFZSA-N
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| InChi Code |
InChI=1S/C39H39Cl2N5O4/c1-20-15-26(16-21(2)35(20)41)50-14-8-9-27-28-11-12-30(40)34(33-23(4)42-44(7)24(33)5)36(28)46-22(3)18-45(38(47)37(27)46)32-19-43(6)31-13-10-25(39(48)49)17-29(31)32/h10-13,15-17,19,22H,8-9,14,18H2,1-7H3,(H,48,49)/t22-/m1/s1
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| Chemical Name |
3-[(4R)-7-chloro-10-[3-(4-chloro-3,5-dimethylphenoxy)propyl]-4-methyl-1-oxo-6-(1,3,5-trimethylpyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2-yl]-1-methylindole-5-carboxylic acid
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| Synonyms |
VU661013; VU 661013; VU-661013
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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 (~175.4 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (2.92 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 (2.92 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. 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. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (2.92 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.4032 mL | 7.0160 mL | 14.0319 mL | |
| 5 mM | 0.2806 mL | 1.4032 mL | 2.8064 mL | |
| 10 mM | 0.1403 mL | 0.7016 mL | 1.4032 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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