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.
Physicochemical Properties
| Molecular Formula | C42H45CLN6O5S2 | |
| Molecular Weight | 813.43 | |
| Exact Mass | 812.258 | |
| Elemental Analysis | C, 62.02; H, 5.58; Cl, 4.36; N, 10.33; O, 9.83; S, 7.88 | |
| CAS # | 852808-04-9 | |
| Related CAS # | ABT-737-d8;1217686-68-4 | |
| PubChem CID | 11228183 | |
| Appearance | Yellow to orange solid powder | |
| Density | 1.4±0.1 g/cm3 | |
| Melting Point | 152-154ºC | |
| Index of Refraction | 1.698 | |
| LogP | 9.21 | |
| Hydrogen Bond Donor Count | 2 | |
| Hydrogen Bond Acceptor Count | 10 | |
| Rotatable Bond Count | 15 | |
| Heavy Atom Count | 56 | |
| Complexity | 1320 | |
| Defined Atom Stereocenter Count | 1 | |
| 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 |
|
| InChi Key | HPLNQCPCUACXLM-PGUFJCEWSA-N | |
| 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 | |
| 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 | |
| Synonyms |
|
|
| HS Tariff Code | 2934.99.9001 | |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
|
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| 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) | |||
| 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]. | |||
| 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]. | |||
| 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. | |||
| 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. | |||
| Animal Protocol |
|
|||
| References |
[1]. Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell. 2006 Nov;10(5):375-88. [2]. Effect of dual inhibition of apoptosis and autophagy in prostate cancer. Prostate. 2012 Sep 1;72(12):1374-81. [3]. Rapid Detection of an ABT-737-Sensitive Primed for Death State in Cells Using Microplate-Based Respirometry.PLoS One. 2012;7(8):e42487. Epub 2012 Aug 3. |
|||
| 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. |
Solubility Data
| Solubility (In Vitro) |
|
|||
| 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. 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. 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 corn oil and mix evenly. Solubility in Formulation 4: 30% Propylene glycol, 5% Tween 80, 65% D5W: 30mg/mL (Please use freshly prepared in vivo formulations for optimal results.) |
| 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 |