TW-37 _Bcl-2 Family 抑制剂 - MedChemExpress

1、Hotline: 400-820-3792Inhibitors Agonists Screening Librarieswww.MedChemETW-37Cat. No.: HY-12020CAS No.: 877877-35-5分式: CHNOS分量: 573.7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 : 42 mg/mL (73.21 mM)* means soluble, but saturatio

2、n unknown.Mass Solvent1 mg 5 mg 10 mg Concentration制备储备液1 mM 1.7431 mL 8.7154 mL 17.4307 mL5 mM 0.3486 mL 1.7431 mL 3.4861 mL10 mM 0.1743 mL 0.8715 mL 1.7431 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 TW-37种有效的 Bcl-2 抑制剂，作于 Mcl-1，Bcl-2 和 Bcl-xL，Ki 值分别为 260，290 和 1110 nM。IC5

3、0 & Target Mcl-1 Bcl-2 Bcl-xL260 nM (Ki) 290 nM (Ki) 1110 nM (Ki)体外研究TW-37 (TW37) is a novel nonpeptide small-molecule inhibitor designed using a structure-based design1/3 Master of Small Molecules 您边的抑制剂师www.MedChemEstrategy. TW-37 targets the BH3-binding groove in Bcl-2 where proapoptotic Bcl-2 pr

4、oteins, such as Bak,Bax, and Bid bind. In fluorescence polarization-based binding assays using recombinant Bcl-2 and Bcl-xLproteins, TW-37 binds to Bcl-2 and Bcl-xL with Ki values of 290 and 1110 nM, respectively. TW-37 has anIC50 of 1.8 M for endothelial cells but shows no cytotoxic effects for fib

5、roblasts at concentrations up to 50 M. The mechanism of TW-37-induced endothelial cell death is apoptosis, in a process mediated bymitochondrial depolarization and activation of caspase-9 and caspase-3. The effect of TW-37 on endothelialcell apoptosis is not prevented by coexposure to the growth fac

6、tor milieu secreted by tumor cells. Inhibition ofthe angiogenic potential of endothelial cells (i.e., migration and capillary sprouting assays) and expression ofthe angiogenic chemokines CXCL1 and CXCL8 are accomplished at subapoptotic TW-37 concentrations(0.005-0.05 M) 1. TW-37 is a potent Bcl-2 an

7、d Mcl-1 inhibitor. In fluorescence polarization-based bindingassays using recombinant Bcl-2, Bcl-xL, and Mcl-1 proteins, TW-37 binds to Bcl-2, Bcl-xL, and Mcl-1 with Kivalues of 290, 1,110 and 260 nM, respectively 2.体内研究 A murine model of humanized vasculature is used to investigate the biological e

8、ffect of TW-37 (TW37) onhuman microvascular endothelial cell in vivo. Using this model, a significant decrease is observed in totalblood vessel number (P 1.PROTOCOLCell Assay 1 The sulforhodamine B (SRB) cytotoxicity assay is used. Briefly, optimal cell density for cytotoxicity assay,2104 to 3104 ce

9、lls per well, is determined by growth curve analysis. HDMECs are seeded at 2.5104 perwell in a 96-well plate and allowed to adhere overnight. Drug or control is diluted in EGM2-MV and layeredonto cells, which are allowed to incubate for times as indicated in the figures. Alternatively, HDMECs arecoi

10、ncubated with TW-37 and 0 to 100 ng/mL recombinant human VEGF (rhVEGF)165 or 0 to 100 ng/mLrecombinant human CXCL8. Cells are fixed on the plates by addition of cold trichloroacetic acid (10% finalconcentration) and incubation for 1 hour at 4C. Cellular protein is stained by addition of 0.4% SRB in

11、1%acetic acid and incubation at room temperature for 30 minutes. Unbound SRB is removed by washing with1% acetic acid and the plates are air dried. Bound SRB is resolubilized in 10 mM unbuffered Tris-base andabsorbance is determined on a microplate reader at 560 nm. Test results are normalized again

12、st initialplating density and drug-free controls. Data are obtained from triplicate wells per condition and arerepresentative of at least three independent experiments 1.MCE has not independently confirmed the accuracy of these methods. They are for reference only.Animal Mice 1Administration 1 Porou

13、s poly L-lactic acid scaffolds (661 mm) with an average pore diameter of 180 m are fabricated. Justbefore implantation, scaffolds are seeded with 1106 HDMECs in a 1:1 Matrigel/EGM2-MV mix. Male severecombined immunodeficient (SCID) mice (CB.17.SCID) are anesthetized with ketamine and xylazine, and t

14、woscaffolds are implanted s.c. in the dorsal region of each mouse. At 10 days after transplantation, six mice pertreatment are treated with 3 mg/kg or 30 mg/kg TW-37 (in vehicle: PBS/Tween 80/ethanol) or vehicle alonei.v. for 5 consecutive days. At the end of the treatment period, mice are euthanize

15、d, and the scaffolds areretrieved, fixed overnight in 10% buffered formaldehyde at 4C, and mounted on glass slides.Immunohistochemistry is done for Factor VIII and microvessels are counted in 6 fields per scaffold and 12scaffolds per treatment at 200 magnification. Alternatively, sections are staine

16、d with H&E and occluded2/3 Master of Small Molecules 您边的抑制剂师www.MedChemEblood vessels are counted.MCE has not independently confirmed the accuracy of these methods. They are for reference only.REFERENCES1. Zeitlin BD, et al. Antiangiogenic effect of TW37, a small-molecule inhibitor of Bcl-2. Cancer Res. 2006 Sep 1;66(17):8698-706.2. Mohammad RM, et al. Preclinical studies of TW-37, a new nonpeptidic small-molecule inhibitor of Bcl-2, in diffuse large cell lymphomaxenograft model reveal drug action on both Bcl-2 a