VU0661013
VU0661013 Basic information
- Product Name:
- VU0661013
- Synonyms:
-
- VU0661013
- VU661013
- 1H-Indole-5-carboxylic acid, 3-[(4R)-7-chloro-10-[3-(4-chloro-3,5-dimethylphenoxy)propyl]-3,4-dihydro-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyrazino[1,2-a]indol-2(1H)-yl]-1-methyl-
- VU0661013, 10 mM in DMSO
- CAS:
- 2131184-57-9
- MF:
- C39H39Cl2N5O4
- MW:
- 712.66
- Mol File:
- 2131184-57-9.mol
VU0661013 Chemical Properties
- Boiling point:
- 906.4±65.0 °C(Predicted)
- Density
- 1.37±0.1 g/cm3(Predicted)
- storage temp.
- Store at -20°C
- solubility
- ≥125mg/mL in DMSO;insoluble in H2O
- form
- Solid
- pka
- 4.44±0.30(Predicted)
- color
- Light yellow to yellow
VU0661013 Usage And Synthesis
Uses
VU661013 is a potent and selective MCL-1 inhibitor.
Biological Activity
vu661013 is a novel, potent, selective mcl-1 inhibitor (ki of 97 ± 30 pm).[1]mcl-1, an anti-apoptotic bcl-2 family member, is commonly upregulated in acute myeloblastic leukemia (aml) cells. targeting anti-apoptotic proteins in aml is a key therapeutic strategy, and mcl-1 is a critical anti-apoptotic oncoprotein. [1]vu661013 reduced expansion of multiple aml cell lines in vitro. venetoclax (a bcl-2 inhibitor) and vu661013 exhibited favorable synergy in several of aml cells lines, venetoclax-resistant aml cells were sensitive to vu661013. [1]vu661013 decreased tumor growth in an in vivo murine model. vu661013 (25mg/kg) and venetoclax (15mg/kg) can be synergistic in patient-derived xenograft transplantation models. [1][1]a novel mcl-1 inhibitor combined with venetoclax rescues venetoclax resistant acute myelogenous leukemia. cancer discov. 2018 sep 5. pmid: 30185627. doi: 10.1158/2159-8290.cd-18-0140
in vivo
VU661013, a novel, potent, selective MCL-1 inhibitor that de-stabilizes BIM/MCL-1 association, leads to apoptosis in AML, and is active in Venetoclax-resistant cells and patient derived xenografts. After establishing disseminated leukemia, NSGS mice are dosed intraperitoneally with 10, 25 or 75 mg/kg of VU661013 daily for 21 days. Weekly chimerism analyses are conducted and the percentage of MV-4-11 cells are quantified in murine peripheral blood using anti-human CD45 (hCD45) and anti-hCD33 monoclonal antibodies. Twenty-eight days post-transplant, vehicle-treated mice have developed large leukemia burdens and thus, mice are sacrificed, and their organs are harvested for analysis. Vehicle mice treated died of xenografted AML, but have no evidence of VU661013-related toxicity in non target organs. VU661013 treatment of disseminated human AML results in a dose-dependent decrease 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 reduces disease-associated splenomegaly (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). In a second MV-4-11 xenograft study, mice are followed until death, and survival is evaluated by Kaplan-Meier analysis. In this study, NSGS mice are treated daily (starting 7 days after transplant) with vehicle only, 15 mg/kg or 75 mg/kg of VU661013. 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].
IC 50
Mcl-1
References
[1] Haley E. Ramsey, et al. A Novel MCL-1 Inhibitor Combined with Venetoclax Rescues Venetoclax Resistant Acute Myelogenous Leukemia. Cancer Discov. August 28, 2018.
VU0661013Supplier
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- 021-52996696，15000506266 15000506266
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- 021-65675885 18964387627
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- 177-54423994 17754423994
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- +86-13301875428
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- 15911056312
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