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Purity: ≥98%
TAE684 (also called NVP-TAE684; TAE-684) is a novel, highly potent and selective small-molecule inhibitor of the ALK (anaplastic lymphoma kinase) tyrosine kinase with potential anticancer activity. In a cell-free assay, it inhibits ALK with an IC50 of 3 nM. TAE 684 inhibits ALK with a sensitivity that is 100 times higher than InsR. With IC50 values between 2 and 10 nM, it exhibits strong anti-proliferative activity against ALK-dependent and ALCL-derived cell lines in vitro.
| Targets |
ALK (IC50 = 2-10 nM)
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| Enzyme Assay |
As a stock solution, 10 mM of GSK1904529A is dissolved in DMSO. The IC50 is determined using proteins tagged with glutathione S-transferase that are expressed by bacteria and encode the intracellular domain of IGF-1R (amino acids 957–1367) and IR (amino acids 979–1382). In order to activate kinases, the enzyme must be preincubated in 50 mM HEPES (pH 7.5), 10 mM MgCl2, 0.1 mg/mL bovine serum albumin, and 2 mM ATP at a final concentration of 2.7 μM. The assay plates are filled with 100 nL/well of diluted GSK1904529A, which has been diluted in DMSO. Kinase reactions that were present (in 10 μL) 0.5 nM activated enzyme, 500 nM substrate peptide (biotin-aminohexylAEEEEYMMMMAKKKK-NH2; QPC), 3 mM DTT, 0.1 mg/mL bovine serum albumin, 1 mM CHAPS, 10 mM MgCl2, and 10 μM ATP. After one hour at room temperature, reactions are terminated using 33 μM EDTA. Using 1 nM europium-conjugated phosphotyrosine antibodies and 7 nM streptavidin Surelight allophycocyanin, time-resolved fluorescence resonance energy transfer is used to measure phosphorylation of peptides. A multilabel reader is used to read plates.
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| Cell Assay |
In 384-well plates, cells are seeded with 2.5×104 cells per well, and they are then incubated for two to three days with TAE684 or DMSO serial dilutions. The Bright-Glo Luciferase Assay System is used to measure luciferase expression, which is a proxy for cell proliferation and survival. To generate IC50 values, use the XLFit software.
Cell Proliferation Assays.[1] Luciferase-expressing Karpas-299, SU-DHL-1, and Ba/F3 cells and transformed Ba/F3 stably expressing NPM-ALK, BCR-ABL, or TEL-kinase fusion constructs were plated in 384-well plates (25,000 cells per well) and incubated with serial dilutions of TAE684 or DMSO for 2–3 days. Luciferase expression was used as a measure of cell proliferation/survival and was evaluated with the Bright-Glo Luciferase Assay System. IC50 values were generated by using XLFit software. Flow Cytometry.[1] Ba/F3 NPM-ALK, Karpas-299, and SU-DHL-1 cells were treated with DMSO or various concentrations of TAE684 for 24, 48, and 72 h before analysis of cell cycle distribution and apoptosis by flow cytometry. Samples were analyzed on a Becton-Dickinson LSRII Flow Cytometer |
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| Animal Protocol |
In order to conduct in vivo compound efficacy studies, female Fox Chase SCIDBeige mice are injected with 1×106 Karpas-299-, Ba/F3 NPM-ALK-, or BCR-ABL-expressing cells via the tail vein 72 hours later. TAE684 resuspended in 10% 1-methyl-2-pyrrolidinone/90% PEG 300 solution is given to mice (n = 10 per group) at 1, 3, and 10 mg/kg once daily for three weeks, or the vehicle solution is given at the same dosing schedule. Bioluminescence imaging is used once a week to track the progression of the disease and the effectiveness of the compound. The disease is confirmed to be widespread by bioluminescence imaging on day 12, at which point dosing is started in order to assess the effectiveness of TAE684 on established disease. For three days, mice with established lymphomas are given either vehicle solution or TAE684 (10 mg/kg) in order to analyze the downstream molecular effects in vivo. Upon completion of therapy, lymph nodes are removed from the mice and subjected to immunoblotting and histological examination.
In Vivo Experiments.[1] For in vivo compound efficacy studies, treatment was initiated 72 h after tail vein injection of 1 × 106 Karpas-299-, Ba/F3 NPM-ALK- or BCR-ABL-expressing cells into female Fox Chase SCIDBeige mice. Mice (n = 10 per group) were administered either TAE684 resuspended in 10% 1-methyl-2-pyrrolidinone/90% PEG 300 solution at 1, 3, and 10 mg/kg once daily for 3 weeks or the vehicle solution at the same dosing schedule. Disease progression and compound efficacy was monitored weekly with bioluminescence imaging. To determine the efficacy of TAE684 on established disease, dosing was initiated on day 12, at which time the disease confirmed to be widespread by bioluminescence imaging. For analysis of downstream molecular effects in vivo, mice with established lymphomas were administered vehicle solution or TAE684 (10 mg/kg) for 3 days. At the end of treatment, mice were killed, and lymph nodes were extracted for immunoblotting and histological analysis. |
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| References |
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| Additional Infomation |
5-chloro-N2-[2-methoxy-4-[4-(4-methyl-1-piperazinyl)-1-piperidinyl]phenyl]-N4-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine is a member of piperidines.
ALK Inhibitor TAE684 is a small molecule inhibitor of the receptor tyrosine kinases (RTKs) anaplastic lymphoma kinase (ALK) and nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), with potential antineoplastic activity. Upon administration, TAE684 binds to and inhibits ALK and NPM-ALK tyrosine kinases, which leads to a disruption of ALK- and NPM-ALK mediated signaling and eventually inhibits tumor cell growth in ALK- and NPM-ALK overexpressing tumor cells. ALK belongs to the insulin receptor superfamily and plays an important role in nervous system development. ALK dysregulation and gene rearrangements are associated with a series of tumors. NPM-ALK is an oncogenic fusion protein associated with ALK-positive anaplastic large cell lymphoma. ALK mutations are also associated with acquired resistance to small molecule tyrosine kinase inhibitors. |
| Molecular Formula |
C30H40CLN7O3S
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| Molecular Weight |
614.2
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| Exact Mass |
613.26
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| Elemental Analysis |
C, 58.66; H, 6.56; Cl, 5.77; N, 15.96; O, 7.81; S, 5.22
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| CAS # |
761439-42-3
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| Related CAS # |
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| PubChem CID |
16038120
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| Appearance |
Pale yellow solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
791.0±70.0 °C at 760 mmHg
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| Flash Point |
432.2±35.7 °C
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| Vapour Pressure |
0.0±2.8 mmHg at 25°C
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| Index of Refraction |
1.622
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| LogP |
2.71
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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 |
9
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| Heavy Atom Count |
42
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| Complexity |
940
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| Defined Atom Stereocenter Count |
0
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| SMILES |
ClC1=C([H])N=C(N=C1N([H])C1=C([H])C([H])=C([H])C([H])=C1S(C([H])(C([H])([H])[H])C([H])([H])[H])(=O)=O)N([H])C1C([H])=C([H])C(=C([H])C=1OC([H])([H])[H])N1C([H])([H])C([H])([H])C([H])(C([H])([H])C1([H])[H])N1C([H])([H])C([H])([H])N(C([H])([H])[H])C([H])([H])C1([H])[H]
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| InChi Key |
QQWUGDVOUVUTOY-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C30H40ClN7O3S/c1-21(2)42(39,40)28-8-6-5-7-26(28)33-29-24(31)20-32-30(35-29)34-25-10-9-23(19-27(25)41-4)37-13-11-22(12-14-37)38-17-15-36(3)16-18-38/h5-10,19-22H,11-18H2,1-4H3,(H2,32,33,34,35)
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| Chemical Name |
5-chloro-2-N-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]-4-N-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine
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| Synonyms |
NVP-TAE684; TAE 684; TAE684; NVP-TAE 684; 5-chloro-N4-(2-(isopropylsulfonyl)phenyl)-N2-(2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-2,4-diamine; TAE684 (NVP-TAE684); NVP-TAE-684; TAE-684
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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: ≥ 0.77 mg/mL (1.25 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 7.7 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: ≥ 0.77 mg/mL (1.25 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 7.7 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: 30% PEG400+0.5% Tween80+5% propylene glycol, pH 4: 10mg/mL |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.6281 mL | 8.1407 mL | 16.2813 mL | |
| 5 mM | 0.3256 mL | 1.6281 mL | 3.2563 mL | |
| 10 mM | 0.1628 mL | 0.8141 mL | 1.6281 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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