ABT-737Bcl-2 inhibitor CAS# 852808-04-9 |
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Quality Control & MSDS
3D structure
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| Cas No. | 852808-04-9 | SDF | Download SDF |
| PubChem ID | 11228183 | Appearance | Powder |
| Formula | C42H45ClN6O5S2 | M.Wt | 813.43 |
| Type of Compound | N/A | Storage | Desiccate at -20°C |
| Solubility | DMSO : 50 mg/mL (61.47 mM; Need ultrasonic) H2O : < 0.1 mg/mL (insoluble) | ||
| Chemical Name | 4-[4-[[2-(4-chlorophenyl)phenyl]methyl]piperazin-1-yl]-N-[4-[[(2R)-4-(dimethylamino)-1-phenylsulfanylbutan-2-yl]amino]-3-nitrophenyl]sulfonylbenzamide | ||
| SMILES | CN(C)CCC(CSC1=CC=CC=C1)NC2=C(C=C(C=C2)S(=O)(=O)NC(=O)C3=CC=C(C=C3)N4CCN(CC4)CC5=CC=CC=C5C6=CC=C(C=C6)Cl)[N+](=O)[O-] | ||
| Standard InChIKey | HPLNQCPCUACXLM-PGUFJCEWSA-N | ||
| Standard InChI | InChI=1S/C42H45ClN6O5S2/c1-46(2)23-22-35(30-55-37-9-4-3-5-10-37)44-40-21-20-38(28-41(40)49(51)52)56(53,54)45-42(50)32-14-18-36(19-15-32)48-26-24-47(25-27-48)29-33-8-6-7-11-39(33)31-12-16-34(43)17-13-31/h3-21,28,35,44H,22-27,29-30H2,1-2H3,(H,45,50)/t35-/m1/s1 | ||
| General tips | For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months. We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months. Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it. |
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| About Packaging | 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial. 2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial. 3. Try to avoid loss or contamination during the experiment. |
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| Shipping Condition | Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request. | ||
| Description | ABT-737 is a BH3 mimetic inhibitor of Bcl-xL, Bcl-2 and Bcl-w with EC50 of 78.7 nM, 30.3 nM and 197.8 nM, respectively; no inhibition observed against Mcl-1, Bcl-B or Bfl-1. | |||||
| Targets | Bcl-xL | Bcl-2 | Bcl-w | |||
| IC50 | 78.7 nM (EC50) | 30.3 nM (EC50) | 197.8 nM (EC50) | |||
| Cell experiment: | |
| Cell lines | Small-cell lung cancer (SCLC) cell (NCI-H889, NCI-H1963, NCI-H1417, NCI-H146, NCI-187, DMS79, NCI-1048, NCI-H82, NCI-H196, H69AR, and DMS114) lines. |
| Preparation method | The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while.Stock solution can be stored below -20°C for several months. |
| Reacting condition | 48 h; 10 μM |
| Applications | The ability of ABT-737 to inhibit cell proliferation with single-agent activity was evaluated against a panel of 11 kinds of SCLC cell lines. Ac-DEVD-AMC, a substrate for activated caspase 3, was used to treatment of H146 cells for 24 h. A dose-dependent increase in apoptosis coincided with a dose-dependent decrease in cell viability following ABT-737 treatment suggesting that ABT-737 inhibits cell proliferation through the induction of apoptosis. |
| Animal experiment: | |
| Animal models | Lymphoma-prone Eμ- myc transgenic mice |
| Dosage form | 75 mg/kg body weight; the tail injection. |
| Application | All B-lymphoid subsets in the ABT-737-treatment (75 mg/kg) cohort were significantly decreased, compared with the vehicle-treated animals, in both the bone marrow and the spleen. Eμ- myc animals treated with ABT-737 contained significantly (**P<0.01) more apoptotic cells in their bone marrow than vehicle-treated mice. |
| Other notes | Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
| References: [1] Tahir S K, Yang X, Anderson M G, et al. Influence of Bcl-2 family members on the cellular response of small-cell lung cancer cell lines to ABT-737[J]. Cancer research, 2007, 67(3): 1176-1183. [2] Kelly P N, Grabow S, Delbridge A R D, et al. Prophylactic treatment with the BH3 mimetic ABT-737 impedes Myc-driven lymphomagenesis in mice[J]. Cell Death & Differentiation, 2012, 20(1): 57-63. | |
ABT-737 Dilution Calculator
ABT-737 Molarity Calculator
| 1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
| 1 mM | 1.2294 mL | 6.1468 mL | 12.2936 mL | 24.5872 mL | 30.7341 mL |
| 5 mM | 0.2459 mL | 1.2294 mL | 2.4587 mL | 4.9174 mL | 6.1468 mL |
| 10 mM | 0.1229 mL | 0.6147 mL | 1.2294 mL | 2.4587 mL | 3.0734 mL |
| 50 mM | 0.0246 mL | 0.1229 mL | 0.2459 mL | 0.4917 mL | 0.6147 mL |
| 100 mM | 0.0123 mL | 0.0615 mL | 0.1229 mL | 0.2459 mL | 0.3073 mL |
| * Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations. | |||||
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ABT-737 is a novel and potent inhibitor of B-cell lymphoma 2 (BCL-2) family proteins, which are critical for cell survival and overexpressed in many tumor cells, with high affinity towards BCL-XL, BCL-2, and BCL-w but no affinity towards less homologous proteins, such as BCL-B, MCL-1, and A1. ABT-737 has shown single-agent activity against lymphoma and small-cell lung cancer as well as substantial antimyeloma activity both in vitro and in vivo. In recent studies, acute myeloid leukemia blast, origenitor, and stem cells are effectively killed by ABT-737 with normal hematopoietic cells intact. The disruption of the BCL-2/BAX complex and BAK-dependent but BIM-independent activation of the intrinsic apoptotic pathway could also be induced by ABT-737.
Reference
Marina Konopleva, Rooha Contractor, Twee Tsao, Ismael Samudio, Peter P. Ruvolo, Shinichi Kitada, Xingming Deng, Dayong Zhai, Yue-Xi Shi, Thomas Sneed, Monique Verhaegen, Maria Soengas, Vivian R. Ruvolo, Teresa McQueen, Wendy D. Schober, Julie C. Watt, Tilahun Jiffar, Xiaoyang Ling, Frank C. Marini, David Harris, Martin Dietrich, Zeev Estrov, James McCubrey, W. Stratford May, John C. Reed, and Michael Andreeff. Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell 2006: 10; 375-388
Suzanne Trudel, A. Keith Stewart, Zhihua Li, Yanjun Shu, Sheng-Ben Liang, Young Trieu, Donna Reece, Josh Paterson, Dingyan Wang, and Xiao-Yan Wen. The Bcl-2 family protein inhibitor,ABT-737, has substantial antimyeloma activity and shows synergistic effect with dexamethasone and melphalan. Clin Cancer Res 2007; 13 (2) 621-629
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Inhibition of MAPKinase pathway sensitizes thyroid cancer cells to ABT-737 induced apoptosis.[Pubmed:28259821]
Cancer Lett. 2017 Jun 1;395:1-10.
Bcl2 family proteins play an important role in the resistance of thyroid cancer cells to apoptosis induced by chemotherapeutic drugs and targeted therapies. BH3-profiling of seven fresh primary papillary thyroid cancer (PTC) tumors showed dependence for survival on Bcl-xL (2/7), Bcl2 (2/7), and Mcl-1 (2/7), while the majority of thyroid cell lines were mainly dependent on Bcl-xL. Targeting Bcl2 family proteins with the BH3 mimetic, ABT-737, while simultaneously inhibiting ERK pathway proteins with PLX4720 and PD325901 was shown to induce significantly high apoptosis in the majority of cell lines (8505c, SW1736, HTh7, BCPAP) and moderate apoptosis in the TPC-1 cell line. In orthotopic thyroid cancer mouse models of 8505c and BCPAP, treatment with the triple drug combination reduced the size of the tumors and showed significantly higher numbers of cells undergoing apoptosis. This treatment increased the expression of pro-apoptotic protein Bim, while decreasing anti-apoptotic protein Mcl-1. Our results suggest that analyzing the results of BH3-profiling along with the mutational status of tumor can reveal an effective therapy for targeted, personalized treatment of aggressive thyroid cancer.
ABT-737 Synergizes with Cisplatin Bypassing Aberration of Apoptotic Pathway in Non-small Cell Lung Cancer.[Pubmed:28319809]
Neoplasia. 2017 Apr;19(4):354-363.
A subset of non-small cell lung cancer (NSCLC), which does not have a druggable driver mutation, is treated with platinum-based cytotoxic chemotherapy, but it develops resistance triggered by DNA damage responses. Here, we investigated the effect of activation of STAT3 by cisplatin on anti-apoptotic proteins and the effectiveness of a co-treatment with cisplatin and a BH3 mimetic, ABT-737. We analyzed the relationship between cisplatin and STAT3 pathway and effect of ABT-737, when combined with cisplatin in NSCLC cells and K-ras mutant mouse models. The synergism of this combination was evaluated by the Chou-Talalay Combination Index method. In vivo activity was evaluated by micro-CT. In NSCLC cells, there was a time and dose-dependent phosphorylation of SRC-JAK2-STAT3 by cisplatin, followed by increased expression of anti-apoptotic molecules. When the expression of the BCL-2 protein family members was evaluated in clinical samples, BCL-xL was most frequently overexpressed. Dominant negative STAT3 suppressed their expression, suggesting that STAT3 mediates cisplatin mediated overexpression of the anti-apoptotic molecules. ABT-737 displaced BCL-xL from mitochondria and induced oligomerization of BAK. ABT-737 itself showed cytotoxic effects and a combination of ABT-737 with cisplatin showed strong synergistic cytotoxicity. In a murine lung cancer model, co-treatment with ABT-737 and cisplatin induced significant tumor regression. These findings reveal a synergistic cytotoxic and anti-tumor activity of ABT-737 and cisplatin co-treatment in preclinical models, and suggest that clinical trials using this strategy may be beneficial in advanced NSCLC.
B-cell lymphoma 2 inhibitor ABT-737 induces Beclin1- and reactive oxygen species-dependent autophagy in Adriamycin-resistant human hepatocellular carcinoma cells.[Pubmed:28351336]
Tumour Biol. 2017 Mar;39(3):1010428317695965.
ABT-737, a B-cell lymphoma 2 homology 3 mimetic, not only induces cell apoptosis by inhibiting the interaction of B-cell lymphoma 2 and Bax but also induces cell autophagy by interrupting the interaction of B-cell lymphoma 2 and Beclin1. Several recent studies have reported that ABT-737 has antitumor efficacy in diverse cancers. However, another study showed that hepatocellular carcinoma cells with high B-cell lymphoma 2 expression were resistant to ABT-737 compared to hepatocellular carcinoma cells with low B-cell lymphoma 2 expression. It was also found that ABT-737-induced autophagy is crucial for drug resistance. Here, we observed that of B-cell lymphoma 2 expression in Adriamycin-resistant human hepatocellular carcinoma HepG2/ADM cells is higher than that in human hepatocellular carcinoma HepG2 cells. Therefore, we further confirmed the mechanism and effect of autophagy induced by ABT-737 on apoptosis in HepG2/ADM cells with high B-cell lymphoma 2 expression. Our results showed that ABT-737 induced apoptosis and autophagy in time- and dose-dependent manner in HepG2/ADM cells, and this ABT-737-induced autophagy was Beclin1-dependent. In addition, we demonstrated that ABT-737 induced reactive oxygen species-mediated autophagy, and the reactive oxygen species-inhibitor N-acetyl-l-cysteine suppressed the reactive oxygen species-induced autophagy and ABT-737-induced increase in HepG2/ADM cell apoptosis. Furthermore, autophagy inhibitors increased HepG2/ADM cell apoptosis. In conclusion, our study further confirms that Beclin1- and reactive oxygen species-dependent autophagy induced by ABT-737 also plays a protective function in HepG2/ADM cells, which show B-cell lymphoma 2 expression higher than that in HepG2 cells.
Combination of ABT-737 and resveratrol enhances DNA damage and apoptosis in human T-cell acute lymphoblastic leukemia MOLT-4 cells.[Pubmed:28366708]
Toxicol In Vitro. 2017 Aug;42:38-46.
ABT-737 belongs to a new class of anticancer agents named BH3 mimetics. ABT-737 competitively binds to surface hydrophobic grooves of anti-apoptotic proteins of Bcl-2 family, counteracting their protective effect. Resveratrol is a natural polyphenol that has been shown to inhibit the proliferation and/or induce apoptosis in a number of different types of cancer cells. The present study was designed to analyze the combined effects of ABT-737 and resveratrol on human acute lymphoblastic leukemia cells. The in vitro cytotoxic activity of these agents against MOLT-4 leukemia cells was determined using the Coulter electrical impedance method, comet assay, and flow cytometry, light microscopy and western blot techniques. The results are the first data showing that ABT-737 combined with resveratrol markedly decreased the cell viability, increased DNA damage, caused the cell cycle perturbation, and synergistically enhanced apoptosis in MOLT-4 cells, when compared to the data obtained after application of the single agent. Moreover, the simultaneous treatment of leukemia cells with ABT-737 and resveratrol resulted in a reduction in mitochondrial membrane potential, an increase of p53 protein level and up-regulation of the Bax/Bcl-2 ratio. The obtained data indicate that the combination of ABT-737 and resveratrol is a promising approach for acute lymphoblastic leukemia treatment that should be further explored.
