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Purity: ≥98%
A-1155463 (A1155463) is a novel highly potent and selective BCL-XL inhibitor with antitumor activity. It exhibits picomolar binding affinity for BCL-XL (Ki ＜0.01 nM) and >1000-fold weaker binding for BCL-2 (Ki = 80 nM), as well as for related proteins BCL-W (Ki = 19 nM) and MCL-1 (Ki > 440 nM). It was found using structure-based design and nuclear magnetic resonance (NMR) fragment screening. A-1155463 is a useful lead structure for future optimization and a great tool molecule for researching the biology of BCL-XL. Over half of the colorectal cell lines exhibit strong growth inhibition in the presence of A-1155463, as indicated by EC50 values ≤0.5 μM. A-1155463 is substantially more potent against BCL-XL-dependent cell lines relative to WEHI-539, while possessing none of its inherent pharmaceutical liabilities. A-1155463 inhibited the growth of the H146 small cell lung cancer xenograft tumor in vivo after several doses and brought about a mechanism-based and reversible thrombocytopenia in mice.
| Targets |
Bcl-xL (Ki = 0.01 nM); Bcl-2 (Ki = 80 nM)
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| ln Vitro |
A-1155463 disturbs BCL-XL-BIM complexes in cells but not BCL-2-BIM complexes. A-1155463 has no detectable cytotoxicity against BCL-2-dependent RS4;11 cells (EC50>5 mM), but it kills BCL-XL-dependent Molt-4 cells (EC50=70 nM). In BCL-XL-dependent H146 cells, A-1155463 causes the classic signs of apoptosis, as shown by the release of cytochrome c from mitochondria, activation of caspase, and accumulation of caspase-dependent sub-G0-G1 DNA content.
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| ln Vivo |
A-1155463 inhibits the growth of the H146 small cell lung cancer xenograft tumor in vivo after several doses and results in a mechanism-based and reversible thrombocytopenia in mice. A rapid and reversible decrease in platelets in SCID-Beige mice after a single IP dose served as evidence of A-1155463's ability to exert in vivo on-target activity. Additionally, A-1155463 treatment provided a modest but statistically significant tumor growth inhibition in SCID-Beige mice bearing tumors. An accompanying manuscript will present thorough mechanistic analyses of A-1155463's activity with appropriate chemotherapy in combination across various tumor types. In nontumor bearing SCID-Beige mice, platelet counts drop significantly after a single 5 mg/kg IP dose of A-1155463 and then return to normal levels within 72 hours. Daily administration of 5 mg/kg IP to SCID-Beige mice for 14 days after they received an inoculation of BCL-XL-dependent H146 tumor cells results in a statistically significant inhibition of tumor growth (maximum tumor growth inhibition = 44%) that is relieved upon stopping the dose.
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| Enzyme Assay |
and selective BCL-XL inhibitor; it binds to BCL-XL with a picomolar affinity (Ki 0.01 nM) while binding to BCL-2 (Ki = 80 nM) and related proteins BCL-W (Ki = 19 nM) and MCL-1 (Ki > 440 nM) is >1000 times weaker.
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| Cell Assay |
A-1155463 is administered to cells in increasing concentrations. Following the manufacturer's instructions, cells are tested for viability using the CellTiter-Glo luminescent cell viability assay after 72 hours. Results are adjusted to reflect untreated cells. With the help of the GraphPad Prism program, EC50 is calculated.
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| Animal Protocol |
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| References |
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| Molecular Formula |
C35H32FN5O4S2
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| Molecular Weight |
669.79
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| Exact Mass |
669.19
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| CAS # |
1235034-55-5
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| Appearance |
Solid
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| SMILES |
CN(C)CC#CC1=CC(=C(C=C1)OCCCC2=C(N=C(S2)N3CCC4=C(C3)C(=CC=C4)C(=O)NC5=NC6=CC=CC=C6S5)C(=O)O)F
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| InChi Key |
SOYCFODXNRVBTI-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C35H32FN5O4S2/c1-40(2)17-6-8-22-14-15-28(26(36)20-22)45-19-7-13-30-31(33(43)44)38-35(47-30)41-18-16-23-9-5-10-24(25(23)21-41)32(42)39-34-37-27-11-3-4-12-29(27)46-34/h3-5,9-12,14-15,20H,7,13,16-19,21H2,1-2H3,(H,43,44)(H,37,39,42)
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| Chemical Name |
2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-5-[3-[4-[3-(dimethylamino)prop-1-ynyl]-2-fluorophenoxy]propyl]-1,3-thiazole-4-carboxylic acid
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| Synonyms |
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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 (3.73 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 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 (3.73 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 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 (3.73 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 | 1.4930 mL | 7.4650 mL | 14.9301 mL | |
| 5 mM | 0.2986 mL | 1.4930 mL | 2.9860 mL | |
| 10 mM | 0.1493 mL | 0.7465 mL | 1.4930 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.
 (a) Kinetics of platelet reduction and rebound following a single IP dose of A-1155463 in SCID-Beige mice.ACS Med Chem Lett.2014Aug 26;5(10):1088-93. |
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X-ray crystal structure of A-1155463 (green) bound to BCL-XL.ACS Med Chem Lett.2014Aug 26;5(10):1088-93. |
 X-ray crystal structure of compound10(green) bound to BCL-XL.ACS Med Chem Lett.2014Aug 26;5(10):1088-93. |
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