VU0661013 - Bcl-2 Family 抑制劑 - 生命科學(xué)試劑 - MedChemExpress

1、Hotline: 400-820-3792Inhibitors Agonists Screening Librarieswww.MedChemEVU0661013Cat. No.: HY-112859CAS No.: 2131184-57-9分式: CHClNO分量: 712.66作靶點: Bcl-2 Family作通路: Apoptosis儲存式: Powder -20C 3 yearsIn solvent -80C 6 months-20C 1 month溶解性數(shù)據(jù)體外實驗 DMSO : 125 mg/mL (175.40 mM)H2O : 40% PEG300 5% Tween-80 4

2、5% salineSolubility: 2.08 mg/mL (2.92 mM); Clear solution2. 請依序添加每種溶劑： 10% DMSO 90% (20% SBE-CD in saline)Solubility: 2.08 mg/mL (2.92 mM); Suspended solution; Need ultrasonic3. 請依序添加每種溶劑： 10% DMSO 90% corn oil1/3 Master of Small Molecules 您邊的抑制劑師www.MedChemESolubility: 2.08 mg/mL (2.92 mM); Clear s

3、olutionBIOLOGICAL ACTIVITY物活性 VU661013種有效的選擇性 MCL-1 抑制劑。IC50 & Target Mcl-1體外研究 VU661013 exhibits a Ki of 9730 pM to human MCL-1 in a TR-FRET assay by displacing a fluorescentlylabeled peptide derived from the pro-apoptotic protein BAK. However, VU661013 does not significantly inhibitBCL-xL (Ki40 M)

4、 or BCL-2 (Ki=0.73 M) 1.體內(nèi)研究 VU661013, a novel, potent, selective MCL-1 inhibitor that de-stabilizes BIM/MCL-1 association, leads toapoptosis in AML, and is active in Venetoclax-resistant cells and patient derived xenografts. Afterestablishing disseminated leukemia, NSGS mice are dosed intraperitone

5、ally with 10, 25 or 75 mg/kg ofVU661013 daily for 21 days. Weekly chimerism analyses are conducted and the percentage of MV-4-11 cellsare quantified in murine peripheral blood using anti-human CD45 (hCD45) and anti-hCD33 monoclonalantibodies. Twenty-eight days post-transplant, vehicle-treated mice h

6、ave developed large leukemia burdensand thus, mice are sacrificed, and their organs are harvested for analysis. Vehicle mice treated died ofxenografted AML, but have no evidence of VU661013-related toxicity in non target organs. VU661013treatment of disseminated human AML results in a dose-dependent

7、 decrease in tumor burden, nearlyeliminating the hCD45+ MV-4-11 cells at the 75 mg/kg dose in the blood (mean, 13.02.2% in vehicle vs7.47.2% in 25mg/kg vs 0.170.12% in 75 mg/kg treated mice), bone marrow (mean, 40.713.9% in vehiclevs 33.464.0 % in 25 mg/kg vs 0.3840.345 in 75 mg/kg treated mice), an

8、d spleen (mean, 46.2213.3% invehicle vs 13.3110.0% in 25 mg/kg vs 1.5881.51% in 75 mg/kg treated mice). Treatment with VU661013reduces disease-associated splenomegaly (mean, vehicle vs. 75mg/kg, 0.170.02 vs 0.090.01g), andamendeding spleen to body weight ratio (vehicle vs 75mg/kg, 0.99 vs 0.50). In

9、a second MV-4-11 xenograftstudy, mice are followed until death, and survival is evaluated by Kaplan-Meier analysis. In this study, NSGSmice 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 treat

10、ed with the 75mg/kg dose (vehicle treated mice=31days, vs 15 mg/kg=32 days, vs 75 mg/kg treated mice=43 Days) 1.PROTOCOLCell Assay 1 To generate cells that are resistant to BCL-2 or MCL-1 inhibition, MV-4-11 cells are treated over the courseof 3 months with gradually increasing concentrations of VEN

11、 (5 nM to 2.5 M) or VU661013 (100 nM to 5 M). Cells are declared to be VEN or VU661013-resistant when they are able to maintain 100% viability in thepresence of these high concentrations (5 M of VU661013 and 2.5 M of VEN) of inhibitors 1.MCE has not independently confirmed the accuracy of these meth

12、ods. They are for reference only.Animal Mice 1Administration 1 Upon establishing microchimerism, mice are treated with either Venetoclax by daily gavage, VU661013 (10,2/3 Master of Small Molecules 您邊的抑制劑師www.MedChemE25 or 75 mg/kg) by daily i.p injection, or vehicle. VU661013 is dissolved in DMSO an

13、d diluted in ethanol,Polyethylene Glycol (PEG), and saline. Venetoclax is dissolved in PEG and ethanol, and diluted with Phosal50 PG. Peripheral blood is assessed weekly for human chimerism. Spleen/body ratio is calculated as organweight (gram) per gram of body weight 1.MCE has not independently confirmed the accuracy of these methods. They are for reference only.REFERENCES1. Haley E. Ramsey, et al. A Novel MCL-1 Inhibitor Combined with Venetoclax Rescues Venetoclax Resistant Acute MyelogenousLeukemia. Cancer Discov. August 28,