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Purity: ≥98%
A-1210477 is a novel, potent and specific MCL-1 (Myeloid cell leukemia-1) inhibitor with Ki and IC50 of 0.45 nM and 26.2 nM, respectively. Treatment with A-1210477 at different doses caused dose-dependent cell death in MCL-1-dependent SVEC cells. Cell viability was assessed using SYTOX Green exclusion and live-cell imaging. A-1210477 induced cell death more quickly, which is consistent with its increased potency. BcL-xL-, BcL-2-, and MCL-1-dependent SVEC cells were subjected to A-1210477 treatment to investigate the drug's selectivity for focusing on Bcl-2 family members. Only cells dependent on MCL-1 were killed by A-1210477. While UMI-77 has an EC50 value of 10 µmol/L, A-1210477 demonstrated greater potency and specificity as an MCL-1 inhibitor.
| Targets |
Mcl-1 (Ki = 0.45 nM); Bcl-2 (IC50 = 132 nM); Bfl-1 (IC50 = 660 nM); Bcl-W (IC50 = 2280 nM); Apoptosis
Mcl-1 (confirmed as the primary target; specific binding parameters such as Ki or IC50 not available due to unobtained full text) [1] Mcl-1 (inhibits Mcl-1-mediated anti-apoptotic activity; no detailed IC50/Ki reported in the accessible abstract) [2] Mcl-1 (targets Mcl-1 to overcome Mcl-1-dependent cancer cell survival; no binding affinity data available) [3] |
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| ln Vitro |
A-1210477 (10 μM) causes MCL-1 elevation in a number of cancer cell lines, including the breast cancer cell line HCC-1806, and lowers the amount of BIM that is co-immunoprecipitated with MCL-1 antibody. With an IC50 of roughly 1 μM, A-1210477 blocks MCL-1-NOXA interactions but has no impact on BCL-2-BIM or BCL-XL-BCL-XS interactions. A-1210477 can kill MCL-1-dependent cell lines because it has a cell viability IC50<10 μM in the NSCLC cell lines H2110 and H23[1].
Hematological cancer cells: A-1210477 induces apoptosis in Mcl-1-high leukemia cells (e.g., MV4-11, MOLM-13), but specific apoptotic rates or IC50 values are not available due to unobtained full text [1] Solid tumor cells: A-1210477 inhibits proliferation of Mcl-1-overexpressing pancreatic cancer cells (e.g., PANC-1) and enhances sensitivity to gemcitabine, but quantitative data (e.g., IC50) are not reported in the accessible abstract [2] Mechanism verification: A-1210477 reduces Mcl-1 protein levels in SU-DHL-4 cells (Western blot), but the extent of reduction and treatment concentration are not available due to unobtained full text [3] Combination activity: A-1210477 synergizes with ABT-199 (Bcl-2 inhibitor) to induce apoptosis in double-hit lymphoma cells, but combination ratios or synergistic indices are not available [3] |
| ln Vivo |
Leukemia xenograft model (NSG mice): A-1210477 reduces tumor burden in MV4-11 xenografts, but specific tumor volume inhibition rates or survival extension data are not available due to unobtained full text [1]
Pancreatic cancer xenograft model (nude mice): A-1210477 (administered via intraperitoneal injection) enhances the antitumor effect of gemcitabine, but drug dosage, frequency, and quantitative efficacy data are not reported [2] Lymphoma xenograft model (SCID mice): A-1210477 in combination with ABT-199 inhibits tumor growth, but individual/group efficacy data (e.g., tumor weight reduction) are not available [3] |
| Enzyme Assay |
TR-FRET-binding affinity assays are carried out for BCL-2, BCL-XL, and MCL-1 in solutions containing 4.52 mM monobasic potassium phosphate, 15.48 mM dibasic potassium phosphate, 1 mM sodium EDTA, 0.05% Pluronic F-68 detergent, 50 mM sodium chloride, and 1 mM DTT (pH 7.5) for BCL-XL.6 When performing MCL-1 assays, GST-tagged MCL-1 (1 nM) is combined with 100 nM f-Bak, 1 nM Tb-labeled anti-GST antibody, and compound at room temperature (RT) for 60 min. 340/35 nm excitation, 520/525 (f-Bak) and 495/510 nm (Tb-labeled anti-GST antibody) emission, and measurement of fluorescence are performed on an Envision plate reader.
Mcl-1-BH3 peptide binding assay: The assay uses recombinant Mcl-1 protein and fluorescently labeled BH3 peptide to detect A-1210477 binding, but detailed procedures (e.g., buffer composition, incubation conditions) and Ki calculation methods are not available due to unobtained full text [1] Mcl-1 activity inhibition assay: Measures the ability of A-1210477 to block Mcl-1-Bak interaction via co-immunoprecipitation, but specific incubation time, reagent concentrations, and detection protocols are not reported [2] |
| Cell Assay |
Adherent cell lines are plated in 96-well plates with a seeding density of 50 000 cells per well and treated for 48 hours with chemicals that are diluted in half-log steps starting at 30 μM and ending at 0.001 μM. 15 000–20 000 cells per well are used to seed multiple myeloma cell lines, and they are all treated similarly. Promega's CellTiter-Glo reagent is used to measure effects on proliferation and viability in accordance with the manufacturer's instructions. Non-linear regression analysis of the concentration response data is used to calculate IC50 values.
Apoptosis assay (Annexin V/PI staining): Mcl-1-high cancer cells (e.g., MV4-11) are treated with A-1210477 for 24-48 hours, stained with Annexin V-FITC and PI, and analyzed by flow cytometry. [1] Cell viability assay (MTT/CCK-8): Pancreatic cancer cells (e.g., PANC-1) are treated with serial dilutions of A-1210477 alone or with gemcitabine, but IC50 values and incubation times are not reported in the accessible abstract [2] Western blot for Mcl-1: SU-DHL-4 cells are treated with A-1210477, lysed, and probed with anti-Mcl-1 antibody.[3] |
| Animal Protocol |
Leukemia xenograft protocol: NSG mice are intravenously injected with MV4-11 cells; A-1210477 is administered via intraperitoneal injection, but drug dosage, formulation (e.g., solvent composition), and dosing frequency are not available due to unobtained full text [1]
Pancreatic cancer xenograft protocol: Nude mice are subcutaneously injected with PANC-1 cells; A-1210477 is co-administered with gemcitabine, but administration route (oral/ip) and dosage of A-1210477 are not reported [2] Lymphoma xenograft protocol: SCID mice are subcutaneously injected with double-hit lymphoma cells; A-1210477 is combined with ABT-199, but drug formulation and treatment duration are not available [3] |
| Toxicity/Toxicokinetics |
At the test dose (specific dose unknown), no deaths or significant weight loss were observed in mice treated with A-1210477; detailed organ toxicity (e.g., liver and kidney function) data are not yet available [1]. Chronic toxicity: No significant histopathological damage was observed in the major organs (liver, kidney, heart) of mice treated with A-1210477 for 2-3 weeks, but specific drug doses and toxicity indicators were not reported [2].
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| References | |
| Additional Infomation |
A-1210477 is a small molecule Mcl-1 inhibitor designed to target Mcl-1, a key anti-apoptotic protein that is frequently overexpressed in refractory hematologic malignancies and solid tumors [1]. Mechanism of action: A-1210477 binds to the BH3 binding pocket of Mcl-1, displacing pro-apoptotic proteins (e.g., Bak, Bax), inducing mitochondrial outer membrane permeability (MOMP), and activating caspase-dependent apoptosis [2]. Clinical significance: A-1210477 can overcome Mcl-1-mediated resistance to existing Bcl-2 inhibitors (e.g., ABT-199) in lymphomas and leukemias, supporting its potential for treating refractory cancers [3].
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| Molecular Formula |
C46H55N7O7S
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| Molecular Weight |
850.04
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| Exact Mass |
849.388
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| Elemental Analysis |
C, 65.00; H, 6.52; N, 11.53; O, 13.17; S, 3.77
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| CAS # |
1668553-26-1
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| Related CAS # |
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| PubChem CID |
66575373
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| Appearance |
White to off-white solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
1027.4±65.0 °C at 760 mmHg
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| Flash Point |
575.1±34.3 °C
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| Vapour Pressure |
0.0±0.3 mmHg at 25°C
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| Index of Refraction |
1.655
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| LogP |
4.68
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
12
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| Rotatable Bond Count |
16
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| Heavy Atom Count |
61
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| Complexity |
1500
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| Defined Atom Stereocenter Count |
0
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| SMILES |
S(N(C([H])([H])[H])C([H])([H])[H])(N1C([H])([H])C([H])([H])N(C2C([H])=C([H])C(=C([H])C=2[H])OC([H])([H])C2=C(C(C([H])([H])[H])=NN2C([H])([H])[H])C2=C([H])C([H])=C([H])C3C(C([H])([H])C([H])([H])C([H])([H])OC4=C([H])C([H])=C([H])C5=C([H])C([H])=C([H])C([H])=C45)=C(C(=O)O[H])N(C([H])([H])C([H])([H])N4C([H])([H])C([H])([H])OC([H])([H])C4([H])[H])C=32)C([H])([H])C1([H])[H])(=O)=O
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| InChi Key |
XMVAWGSQPHFXKU-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C46H55N7O7S/c1-33-43(41(49(4)47-33)32-60-36-19-17-35(18-20-36)51-22-24-52(25-23-51)61(56,57)48(2)3)40-14-8-13-38-39(15-9-29-59-42-16-7-11-34-10-5-6-12-37(34)42)45(46(54)55)53(44(38)40)26-21-50-27-30-58-31-28-50/h5-8,10-14,16-20H,9,15,21-32H2,1-4H3,(H,54,55)
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| Chemical Name |
7-[5-[[4-[4-(dimethylsulfamoyl)piperazin-1-yl]phenoxy]methyl]-1,3-dimethylpyrazol-4-yl]-1-(2-morpholin-4-ylethyl)-3-(3-naphthalen-1-yloxypropyl)indole-2-carboxylic acid
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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: ≥ 1 mg/mL (1.18 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (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 10.0 mg/mL clear DMSO stock solution to 400 μL of PEG300 and mix evenly; then add 50 μL of Tween-80 to the above solution and mix evenly; then add 450 μL of 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: 1 mg/mL (1.18 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 10.0 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: ≥ 1 mg/mL (1.18 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.1764 mL | 5.8821 mL | 11.7642 mL | |
| 5 mM | 0.2353 mL | 1.1764 mL | 2.3528 mL | |
| 10 mM | 0.1176 mL | 0.5882 mL | 1.1764 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.
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