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.
Physicochemical Properties
| Molecular Formula | C39H39CL2N5O4 |
| Molecular Weight | 712.66406750679 |
| Exact Mass | 711.24 |
| Elemental Analysis | C, 65.73; H, 5.52; Cl, 9.95; N, 9.83; O, 8.98 |
| CAS # | 2131184-57-9 |
| Related CAS # | 2131184-57-9 |
| PubChem CID | 134828256 |
| Appearance | Light yellow to yellow solid powder |
| LogP | 8.1 |
| Hydrogen Bond Donor Count | 1 |
| Hydrogen Bond Acceptor Count | 5 |
| Rotatable Bond Count | 8 |
| Heavy Atom Count | 50 |
| Complexity | 1230 |
| Defined Atom Stereocenter Count | 1 |
| 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 |
| InChi Key | BSAYHBZFNXDOIJ-JOCHJYFZSA-N |
| 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 |
| 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 |
| Synonyms | VU661013; VU 661013; VU-661013 |
| HS Tariff Code | 2934.99.9001 |
| 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) |
Biological Activity
| Targets | Mcl-1 (Ki = 97 pM) |
| 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]. |
| 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]. |
| 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]. |
| References |
[1]. A Novel MCL-1 Inhibitor Combined with Venetoclax Rescues Venetoclax Resistant Acute Myelogenous Leukemia. Cancer Discov. August 28, 2018. |
Solubility Data
| Solubility (In Vitro) | DMSO: ≥ 125 mg/mL (~175.4 mM) |
| 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. 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. 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 | 1.4032 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 |