A-1210477 - Mcl-1 抑制劑 - 生命科學(xué)試劑 - MedChemExpress

1、Hotline: 400-820-3792Inhibitors Agonists Screening Librarieswww.MedChemEA-1210477Cat. No.: HY-12468CAS No.: 1668553-26-1分式: CHNOS分量: 850.04作靶點(diǎn): Bcl-2 Family作通路: Apoptosis儲(chǔ)存式: Powder -20C 3 years4C 2 yearsIn solvent -80C 6 months-20C 1 month溶解性數(shù)據(jù)體外實(shí)驗(yàn) DMSO : 10 mg/mL (11.76 mM; Need ultrasonic)H2O : 4

2、0% PEG300 5% Tween-80 45% salineSolubility: 1 mg/mL (1.18 mM); Clear solution2. 請(qǐng)依序添加每種溶劑： 10% DMSO 90% (20% SBE-CD in saline)Solubility: 1 mg/mL (1.18 mM); Suspended solution; Need ultrasonic3. 請(qǐng)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: 1 mg/mL (1.1

3、8 mM); Clear solutionBIOLOGICAL ACTIVITY物活性 A-1210477種有效，選擇性的 MCL-1 抑制劑，Ki 值為 0.45 nM。IC50 & Target Mcl-1 Bcl-2 Bfl-1 Bcl-W0.45 nM (Ki) 132 nM (Ki) 660 nM (Ki) 2280 nM (Ki)體外研究 A-1210477 (10M) reduces the amount of BIM co-immunoprecipitated with MCL-1 antibody, and triggersMCL-1 elevation in a varie

4、ty of cancer cell lines, including the breast cancer cell line HCC-1806. A-1210477inhibits MCL-1-NOXA interactions with an IC50 of approximately 1M, while having no effect on BCL-2-BIMor BCL-XL-BCL-XS interactions. The NSCLC cell lines H2110 and H23 are sensitive to A-1210477 with cellviability IC50

5、 1. A-1210477 induces extensive concentration-dependent apoptosis in H929 cells following abrief (4h) exposure. A-1210477 interacts with MCL-1 with Kd of appr 740nM. A-1210477 (10M) inducesextensive mitochondrial fragmentation in a DRP-1-dependent manner 2. A-1210477 upregulates MCL-1expression in B

6、RAF-mutant CRC cells and in the melanoma cell line A375 in a dose-dependent manner. A-1210477 releases BAK from MCL-1 and cobimetinib induces BIM that is required for BAX activation 3. A-1210477 (0, 5, 10 and 15M) has minimal effect on cell viability but substantially sensitizes resistantBCL2High NH

7、L cell lines to navitoclax 4.PROTOCOLKinase Assay 1 TR-FRET-binding affinity assays are performed for BCL-2, BCL-XL, and MCL-1 in 4.52mM monobasicpotassium phosphate, 15.48mM dibasic potassium phosphate, 1mM sodium EDTA, 0.05% Pluronic F-68detergent, 50mM sodium chloride, and 1mM DTT (pH 7.5) for BC

8、L-XL.6 For MCL-1 assays, GST-taggedMCL-1 (1nM) is mixed with 100nM f-Bak, 1nM Tb-labeled anti-GST antibody, and compound at roomtemperature (RT) for 60min. Fluorescence is measured on an Envision plate reader using a 340/35nmexcitation filter and 520/525 (f-Bak) and 495/510nm (Tb-labeled anti-GST an

9、tibody) emission filters.MCE has not independently confirmed the accuracy of these methods. They are for reference only.Cell Assay 1 Adherent cell lines are seeded at 50000 cells per well in 96-well plates and treated for 48h with compoundsdiluted in half-log steps starting at 30M and ending at 0.00

10、1M. Multiple myeloma cell lines are seeded at15000-20000 cells per well and treated similarly. Effects on proliferation and viability are determined usingCellTiter-Glo reagent from Promega according to the manufacturers instructions. IC50 values are determinedby non-linear regression analysis of the

11、 concentration response data.MCE has not independently confirmed the accuracy of these methods. They are for reference only.戶使本產(chǎn)品發(fā)表的科研獻(xiàn) Cell Death Differ. 2019 Mar;26(3):470-486. Open Biol. 2016 Aug;6(8). pii: 160134.2/3 Master of Small Molecules 您邊的抑制劑師www.MedChemE Clin Res Hepatol Gas. 2018. Dec.

12、Leuk Lymphoma. 2019 Jan 10:1-11.See more customer validations on HYPERLINK / www.MedChemEREFERENCES1. Leverson JD, et al. Potent and selective small-molecule MCL-1 inhibitors demonstrate on-target cancer cell killing activity as singleagents and in combination with ABT-263 (navitoclax). Cell Death D

13、is. 2015 Jan 15;6:e1590.2. Milani M, et al. DRP-1 is required for BH3 mimetic-mediated mitochondrial fragmentation and apoptosis. Cell Death Dis. 2017 Jan12;8(1):e25523. Kawakami H, et al. Mutant BRAF Upregulates MCL-1 to Confer Apoptosis Resistance that Is Reversed by MCL-1 Antagonism andCobimetinib in Colorectal Cancer. Mol Cancer Ther. 2016 Dec;15(12):3015-30274. Phillips DC, et al. Loss in MCL-1 function sensitizes non-Hodgkins lymphoma cell lines to the BCL-2-selective inhibitor venetoclax (ABT-199). Blood Cancer J. 2015 Nov 13;5