A-385358 - Bcl-2 Family 抑制剂 - 生命科学试剂 - MedChemExpress

1、Hotline: 400-820-3792Inhibitors Agonists Screening Librarieswww.MedChemEA-385358Cat. No.: HY-16014CAS No.: 406228-55-5分式: CHNOS分量: 639.83作靶点: Bcl-2 Family作通路: Apoptosis储存式: Powder -20C 3 years4C 2 yearsIn solvent -80C 6 months-20C 1 month溶解性数据体外实验 DMSO : 125 mg/mL (195.36 mM; Need ultrasonic and war

2、ming)Mass Solvent1 mg 5 mg 10 mg Concentration制备储备液1 mM 1.5629 mL 7.8146 mL 15.6292 mL5 mM 0.3126 mL 1.5629 mL 3.1258 mL10 mM 0.1563 mL 0.7815 mL 1.5629 mL请根据产品在不同溶剂中的溶解度，选择合适的溶剂配制储备液，并请注意储备液的保存式和期限。BIOLOGICAL ACTIVITY物活性 A-385358Bcl-XL 的个选择性抑制剂，对于 Bcl-XL 和 Bcl-2 的 Ki 值分别为 0.80 和 67 nM。IC50 & Target

3、 Bcl-xL Bcl-20.8 nM (Ki) 67 nM (Ki)体外研究A-385358 is a selective inhibitor of Bcl-XL with Kis of 0.80 and 67 nM for Bcl-XL and Bcl-2, respectively, influorescence polarization assays. Treatment of IL-3-deprived FL5.12/Bcl-XL cells for 24 hours with A-3853581/3 Master of Small Molecules 您边的抑制剂师www.MedC

4、hemEresults in cell killing with an EC50 of 0.470.05 M (n=68). This effect is accompanied by an increase incaspase-3 activity. Consistent with the greater affinity for the Bcl-XL versus Bcl-2 hydrophobic grooves, theEC50 of A-385358 for IL-3-depleted FL5.12/Bcl-2 cells (1.90.1 M; n=55) is 4-fold hig

5、her relative to thecytokine-deprived FL5.12/Bcl-XL cells. In addition, A-385358 is more effective at stimulating cytochrome crelease from mitochondria isolated from FL5.12/Bcl-XL versus Bcl-2 cells 1.体内研究 The combination of A-385358 given at 100 mg/kg/d plus the lower dose of paclitaxel produces a s

6、ignificantreduction in tumor growth (%T/C) compare with paclitaxel monotherapy. This combination also yields a100% increase in time for tumors to reach 900 mm3 (%ILS) compare with vehicle control. Maximal efficacyis observed during the dosing period for A-385358, with slow but steady increase in the

7、 tumor growth aftertermination of treatment. The combination of A-385358 at 75 mg/kg/d plus paclitaxel at 30 mg/kg/d is alsowell tolerated and inhibits tumor growth rate by nearly 80%. Significant effects on tumor growth relative topaclitaxel monotherapy are observed with doses as low as 50 mg/kg/d

8、1.PROTOCOLKinase Assay 1 FL5.12 cells suspended in EMB growth medium containing 4% fetal bovine serum (FBS) are incubated at37C for 1 hour in 10 M A-385358. Compound concentration is determined by high-performance liquidchromatography before and after the 1-hour incubation following brief centrifuga

9、tion. To analyze membrane-bound fractions following compound incubation, cells are washed once with 10 volumes of cold PBS andlysed with 4 mL of water. A-385358 concentration is determined from aliquots of lysate before and aftercentrifugation 1.MCE has not independently confirmed the accuracy of th

10、ese methods. They are for reference only.Cell Assay 1 A549 cells (1105) are plated in 96-well plates in medium containing 10% fetal bovine serum. Followingattachment, A-385358 is added to one set of wells (final concentration of 50 M in 10% FBS) and medium isadded to another set. 3HPaclitaxel (5 M;

11、0.5 Ci/mL final concentration) is added to all wells and the cellsare incubated at 37C for various periods of time. For washout experiments, cells are exposed first to3Hpaclitaxel for 2 hours. The cells are washed once with medium and then incubated with fresh mediumwith or without 50 M A-385358 at

12、37C for various periods of time 1.MCE has not independently confirmed the accuracy of these methods. They are for reference only.Animal For efficacy studies, male CD-1 nude mice are inoculated with a 1:5 dilution of tumor brei in 50% MatrigelAdministration 1 and analysis is conducted. A-385358 is de

13、livered in a vehicle containing 5% Tween 80, 20% propyleneglycol, and 75% PBS (pH 3.8). Paclitaxel is formulated according to the recommendations of themanufacturer. For combination therapy of paclitaxel plus A-385358, both drugs are administered i.p. with thepaclitaxel given several hours before tr

14、eatment with A-385358 (except for immunohistochemistry studieslooking at expression of MPM-2 and caspase-3 wherein the two drugs are given simultaneously) 1.MCE has not independently confirmed the accuracy of these methods. They are for reference only.REFERENCES1. Shoemaker AR, et al. A small-molecule inhibitor of Bcl-XL potentiates the activity of cytotoxic drugs in vitro and in vivo. Cancer Res.2/3 Master of Small Molecules 您边的抑制剂师www.MedChemE2006 Sep