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| 5mg |
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Purity: ≥98%
TAK-659 (TAK659) hydrochloride is a novel, potent, highly selective and orally bioavailable spleen tyrosine kinase (Syk) inhibitor (IC50 = 3.2 nM) with the potential for the treatment of chronic lymphocytic leukemia (CLL). In a cell proliferation assay, TAK-659 exhibits inhibition toward a SYK-dependent cell line (OCILY10). The growth of the FLT3-ITD dependent cell lines, MV4-11 and MOLM-13, is demonstrated to be inhibited by TAK-659, whereas the ALL cell line WT FLT3 RS4-11 and the Burkitt's lymphoma cell line RA1 are not responsive to TAK-659. While TAK-659 is not cytotoxic for adherent primary or solid tumor cell lines, its sensitivity in B cell lymphomas is linked to mutations affecting SYK activity. TAK-659 prevents downstream signaling molecules and Syk from being activated by the microenvironment, while leaving T cell protein homolog ZAP-70 unaffected. Interestingly, TAK-659 also inhibits CLL cell migration toward BMSC, CXCL12, and CXCL13, thereby nullifying the pro-survival, proliferative, chemoresistant, and activation effects facilitated by the microenvironment.
| Targets |
Syk (IC50 = 3.2 nM); FLT3 (IC50 = 4.6 nM)
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| ln Vitro |
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| ln Vivo |
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| Cell Assay |
Cells are kept in a humidified environment with 5-8% CO2 at 37°C. The soluble tetrazolium salt, MTS, is used to measure the inhibition of cell viability in a panel of solid tumor and hematological cell lines. Before adding compounds or a DMSO vehicle, cells are seeded in 96-well tissue culture plates and incubated for 24 hours at 37°C with 5% CO2. The MTS conversion by metabolically active cells is measured using a Thermomax microplate reader by measuring the OD490 nm of the wells after 72 or 96 hours of compound incubation. Cells are treated with a range of serial compound dilutions in duplicate in order to create concentration-response curves. Compound dilutions are made in DMSO before they are added to cells. Cells receive equal additions of DMSO, with a final concentration of 0.5%. Following background correction and normalization against DMSO-treated cells, these cell viability results are curve-fitted using nonlinear regression analysis to determine EC50 values.
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| Animal Protocol |
LMP2A/MYC double transgenic mice
100 mg/kg/day Oral gavage; for 10 days |
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| References |
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| Molecular Formula |
C17H22CLFN6O
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| Molecular Weight |
380.8476
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| Exact Mass |
380.152
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| CAS # |
1952251-28-3
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| Related CAS # |
TAK-659;1312691-33-0
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| PubChem CID |
129626432
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| Appearance |
White to off-white solid
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
26
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| Complexity |
508
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| Defined Atom Stereocenter Count |
2
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| SMILES |
CN1C=C(C=N1)C2=NC(=C(C3=C2C(=O)NC3)F)N[C@@H]4CCCC[C@@H]4N.Cl
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| InChi Key |
PTCFBXMEFRIEGV-ZVWHLABXSA-N
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| InChi Code |
InChI=1S/C17H21FN6O.ClH/c1-24-8-9(6-21-24)15-13-10(7-20-17(13)25)14(18)16(23-15)22-12-5-3-2-4-11(12)19;/h6,8,11-12H,2-5,7,19H2,1H3,(H,20,25)(H,22,23);1H/t11-,12+;/m0./s1
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| Chemical Name |
6-[[(1R,2S)-2-aminocyclohexyl]amino]-7-fluoro-4-(1-methylpyrazol-4-yl)-1,2-dihydropyrrolo[3,4-c]pyridin-3-one;hydrochloride
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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 Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture. |
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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) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.6257 mL | 13.1285 mL | 26.2571 mL | |
| 5 mM | 0.5251 mL | 2.6257 mL | 5.2514 mL | |
| 10 mM | 0.2626 mL | 1.3129 mL | 2.6257 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 | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT02954406 | Terminated | Drug: TAK-659 Drug: Bendamustine |
Lymphoma, Non-Hodgkin | Millennium Pharmaceuticals, Inc. | March 5, 2017 | Phase 1 |
 Syk inhibition by TAK-659 downregulates BCR signalling in Ramos and primary CLL cells.Oncotarget.2017 Jan 3;8(1):742-756. |
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 TAK-659 induces higher degree of apoptosis than R406 in primary CLL cells.Oncotarget.2017 Jan 3;8(1):742-756. |
 Treatment with TAK-659 effectively abrogates the co-culture-induced proliferation and activation of primary CLL cells.Oncotarget.2017 Jan 3;8(1):742-756. |
 Syk inhibition by TAK-659 inhibits chemotaxis of primary CLL cells toward CXCL12, CXCL13 and BMSC.Oncotarget.2017 Jan 3;8(1):742-756. |
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 The combination of TAK-659 with fludarabine, ibrutinib or idelalisib synergistically induces apoptosis in proliferative CLL cells.Oncotarget.2017 Jan 3;8(1):742-756. |
 TAK-659 does not inhibit TCR downstream signaling or expression of activation molecules in T cells.Oncotarget.2017 Jan 3;8(1):742-756. |
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