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Purity: ≥98%
ABT-737 is a novel, potent, selective and orally bioavailable BH3 mimetic inhibitor of Bcl-xL, Bcl-2 and Bcl-w with EC50 of 78.7 nM, 30.3 nM and 197.8 nM in enzymatic assays, respectively. Mcl-1, Bcl-B, Bfl-1, etc. are not inhibited by it. It is currently undergoing a Phase 2 clinical trial to treat cancer. ABT-737 has demonstrated significant antimyeloma activity both in vitro and in vivo, as well as single-agent activity against lymphoma and small-cell lung cancer. ABT-737 works as a BCL-2 inhibitor by mimicking BH3, which is the native ligand of BCL-2. It prevents the anti-apoptotic BCL-2 protein, causing CLL cells to undergo programmed cell death.
| Targets |
Bcl-2 (EC50=30.3 nM); Bcl-xL (EC50=78.7 nM); Bcl-W (EC50=197.8 nM); Bcl-B (EC50=1820 nM); Bfl-1 (EC50>10 μM); Mcl-1 (EC50>10 μM)
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| ln Vitro |
ABT-737 binds to the antiapoptotic BCL-2 family members BCL-2, BCL-XL, and BCL-W with high affinity (Ki 1 nM), but weakly (Ki > 460 nM) to MCL-1 and BFL-1. The BH3-binding groove of BCL-XL and BCL-2 is bound by ABT-737[1].
ABT-737 (100 nM; 1-72 hours) induces apoptosis and synergizes with chemotherapy in HL-60 cells[1].
ABT-737 (5, 7.5, and 10 M; 72 h) kills 80% of the HCT116 cells. ABT-737 cannot harm the BAX knockout variant at all[1].
ABT-737 has no effect on cell cycle distribution. In HL-60 leukemic cells, ABT-737 prevents BCL-2/BAX heterodimerization and causes a change in BAX conformation[1].
IABT-737 induces a BAX/BAK-dependent impairment of maximal O2 consumption rate in sensitive cells. An ABT-737-sensitive primed for death state is induced by stable BCL-2 overexpression in MCF10A cells. In B-cell lymphoma cells, ABT-737 causes a dose-dependent impairment of the maximal oxygen consumption rate[3].
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| ln Vivo |
ABT-737 (20, 30 mg/kg/day; i.p.; for 21 days) suppresses the leukemia burden by 48% and 53% at the 20 and 30 mg/kg dose levels, respectively, in four- to six-week-old CB.17 Scid mice were given KG-1 cells from human leukemia[1].
ABT-737 significantly extends survival of mice in this aggressive leukemia model[1].
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| Enzyme Assay |
To determine the binding affinity of GST-BCL-2 family proteins to the FITC-conjugated BH3 domain of BIM (FITC-Ahx-DMRPEIWIAQELRRIGDEFNAYYAR), FPAs are performed as follows. Briefly, 100 nM of GST-BCL-2 family fusion proteins are incubated with serial dilutions of ABT-737 in PBS for 2 min. Then, 20 nM of FITC-BIM BH3 peptide (FITC-Ahx-DMRPEIWIAQELRRIGDEFNAYYAR) is added. Fluorescence polarization is measured using an Analyst TM AD Assay Detection System after 10 min using the 96-well black plate. IC50s are determined using GraphPad Prism software.
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| Cell Assay |
Cells are treated with ABT-737, ABT-263, or vehicle (DMSO) for 4 h in XF24 assay medium (6×104 MCF10A cells, see medium composition below) or RPMI 1640 medium (1×106 B-cell lymphoma cells) and apoptosis is analyzed by Annexin-V-binding/PI exclusion or by sub-diploid nuclei determination. FACS analysis is performed on Becton Dickinson FACScan or FACScalibur instruments. Data analysis is performed with CellQuest software.
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| Animal Protocol |
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| References |
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| Additional Infomation |
ABT-737 is a biphenyl that is 4-chloro-1,1'-biphenyl substituted by a (4-{4-[(4-{[(2R)-4-(dimethylamino)-1-(phenylsulfanyl)butan-2-yl]amino}-3-nitrobenzene-1-sulfonyl)carbamoyl]phenyl}piperazin-1-yl)methyl group at position 2'. It is a BH3-mimetic drug which targets the anti-apoptotic B-cell lymphoma-2 (BCL-2) family proteins, including BCL-2, BCL-xL, and BCL-w, and induces apoptosis in cancer cells. It has a role as an anti-allergic agent, an anti-inflammatory agent, an antineoplastic agent, an apoptosis inducer and a B-cell lymphoma 2 inhibitor. It is a member of biphenyls, a member of monochlorobenzenes, a C-nitro compound, an aromatic amine, a N-arylpiperazine, a N-sulfonylcarboxamide, an aryl sulfide, a secondary amino compound and a tertiary amino compound.
An inhibitor of members of the Bcl‑2 family of apoptosis regulators. BH3 Mimetic ABT-737 is an orally bioavailable, selective small molecule B-cell lymphoma 2 (Bcl-2) Homology 3 (BH3) mimetic, with potential pro-apoptotic and antineoplastic activities. ABT-737 binds to the hydrophobic groove of multiple members of the anti-apoptotic Bcl-2 protein family, including Bcl-2, Bcl-xl and Bcl-w. This inhibits the activity of these pro-survival proteins and restores apoptotic processes in tumor cells, via activation of Bak/Bax-mediated apoptosis. The pro-survival Bcl-2 proteins are overexpressed in many cancers and play important roles in the regulation of apoptosis. Their expression is associated with increased drug resistance and tumor cell survival. ABT-737 does not inhibit the pro-survival proteins Mcl-1, Bcl-B, Bfl-1 (A1); therefore, tumors that overexpress these Bcl-2 family proteins are resistant to ABT-737. |
| Molecular Formula |
C42H45CLN6O5S2
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| Molecular Weight |
813.43
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| Exact Mass |
812.258
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| Elemental Analysis |
C, 62.02; H, 5.58; Cl, 4.36; N, 10.33; O, 9.83; S, 7.88
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| CAS # |
852808-04-9
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| Related CAS # |
ABT-737-d8;1217686-68-4
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| PubChem CID |
11228183
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| Appearance |
Yellow to orange solid powder
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| Density |
1.4±0.1 g/cm3
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| Melting Point |
152-154ºC
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| Index of Refraction |
1.698
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| LogP |
9.21
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
10
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| Rotatable Bond Count |
15
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| Heavy Atom Count |
56
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| Complexity |
1320
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| Defined Atom Stereocenter Count |
1
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| SMILES |
C(N1CCN(C2C=CC(C(=O)NS(C3C=CC(N[C@H](CCN(C)C)CSC4C=CC=CC=4)=C([N+](=O)[O-])C=3)(=O)=O)=CC=2)CC1)C1=CC=CC=C1C1C=CC(Cl)=CC=1
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| InChi Key |
HPLNQCPCUACXLM-PGUFJCEWSA-N
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| InChi Code |
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
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| Chemical Name |
(R)-4-(4-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((4-(dimethylamino)-1-(phenylthio)butan-2-yl)amino)-3-nitrophenyl)sulfonyl)benzamide
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (3.07 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: 2.5 mg/mL (3.07 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (3.07 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 30% Propylene glycol, 5% Tween 80, 65% D5W: 30mg/mL |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.2294 mL | 6.1468 mL | 12.2936 mL | |
| 5 mM | 0.2459 mL | 1.2294 mL | 2.4587 mL | |
| 10 mM | 0.1229 mL | 0.6147 mL | 1.2294 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Status | Interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT01440504 | Completed | Other: culture ex vivo with exposure to different the rapeutic agents alone or in combination. |
Ovarian Cancer | Centre Francois Baclesse | April 2010 | |
| NCT00902018 | Completed | Drug: Eltrombopag Drug: Romiplostim Other: healthy controls |
Immune Thrombocytopenia | Weill Medical College of Cornell University |
January 2009 | Phase 2 |
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