VU661013

Mcl-1 (Ki = 97 pM)

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].

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].

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].

[1]. A Novel MCL-1 Inhibitor Combined with Venetoclax Rescues Venetoclax Resistant Acute Myelogenous Leukemia. Cancer Discov. August 28, 2018.

C39H39CL2N5O4

712.672

711.24

C, 65.73; H, 5.52; Cl, 9.95; N, 9.83; O, 8.98

2131184-57-9

2131184-57-9

Solid powder

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

BSAYHBZFNXDOIJ-JOCHJYFZSA-N

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

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

VU661013; VU 661013; VU-661013

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: ≥ 125 mg/mL (~175.4 mM)

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.

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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.

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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.

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 (Please use freshly prepared in vivo formulations for optimal results.)