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Purity: ≥98%
TAK-733 is a novel, potent, selective and orally bioavailable allosteric (non-ATP competitive) MEK inhibitor with potential anticancer activity. It has an IC50 of 3.2 nM for MEK1 and has no effect on Abl1, AKT3, c-RAF, CamK1, CDK2, or c-Met. TAK-733 has advanced to Phase I clinical trials for the treatment of cancer and may have antineoplastic activity. It specifically binds to and inhibits the activity of MEK1/2, preventing the activation of MEK1/2-dependent effector proteins and transcription factors, which may inhibit growth factor-mediated cell signaling and tumor cell proliferation. In mouse xenograft models of human cancer (melanoma, colorectal, NSCLC, pancreatic, and breast cancer), TAK-733 has been shown to significantly reduce tumor activity.
| Targets |
MEK (IC50 = 3.2 nM)
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| ln Vitro |
TAK-733 exhibits potent enzymatic and cellular activity, with an IC50 of 3.2 nM against constitutively active MEK enzyme and an EC50 of 1.9 nM against ERK phosphorylation in cells. Other kinases, receptors, and ion channels tested with inhibitor concentrations up to 10 μM are unaffected by TAK-733. TAK-733 exhibits high permeability and high microsomal stability across species, and it is found to moderately bind plasma protein (about 97% for humans and 96% for mice). Up to 30 μM, it doesn't inhibit P450s[1]. TAK-733 exhibits widespread activity in the majority of melanoma cell lines, with relative resistance noted at IC50 > 0.1 μM in vitro. For 72 hours, 34 different melanoma cell lines are incubated with progressively higher doses of TAK-733. Seven of the 34 cell lines are wild-type, while 27 have the BRAFV600E mutation. SRB proliferation assays were carried out, and the IC50 concentrations obtained allowed cell lines to be divided into three groups: relatively resistant, intermediate, and highly sensitive. Based on an IC50 that differs by at least 10 fold[2,] relatively resistant and highly sensitive lines are assigned.
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| ln Vivo |
TAK-733's pharmacokinetics are examined in naked mice, rats, dogs, and monkeys. All species exhibit low clearance and high oral bioavailability. In mouse xenograft models of human cancer, including melanoma, colorectal, NSCLC, pancreatic, and breast cancer models, TAK-733 exhibits broad antitumor activity[1]. In the mice (5/group), implanted with A375 cells, daily oral administration of 1, 3, 10, and 30 mg/kg of TAK-733 for 14 days (Days 10 to 23) results in a delay in tumor growth. On an intermittent dosing schedule of 3 days per week for 2 weeks (Days 10, 13, 15, 17, 20, and 22), TAK-733 (35, 70, 100, and 160 mg/kg) also significantly inhibits tumor growth. In mice given 30 mg/kg of TAK-733 daily and mice given 160 mg/kg of TAK-733 intermittently, three partial regressions (PR) with a 60% response rate were seen. Mice that were given intermittent doses of 70, 100, and 160 mg/kg of TAK-733 also showed responses, complete regressions (CR), and partial regressions (PR). The tumor regression rate is more pronounced with the intermittent administration regimen; the largest reduction in tumor volume is seen at 160 mg/kg (57.29%), compared to a maximum reduction of 46.97% at 30 mg/kg once daily. In mice given 3, 10, and 30 mg/kg once daily or 35, 70, 100, and 160 mg/kg intermittently, tumor growth is significantly (p<0.05 for %T/C, Student's t-test) inhibited by the final day of administration[2].
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| Enzyme Assay |
K-733 is highly potent and selective MEK allosteric site inhibitor with IC50 of 3.2 nM. TAK-733 shows potent enzymatic and cell activity with an EC50 of 1.9 nM against ERK phosphorylation in cells.
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| Cell Assay |
The cutaneous melanoma cell lines are transferred to 96 well flat bottom plates with lids while they are still in the logarithmic growth phase. Prior to being exposed to TAK-733 at increasing concentrations (10, 20, 30, 40, 50, 60, 70, 80, 90, and 100 nM) for 72 hours, 100 μL cell suspensions containing 2000–3000 viable cells are plated into each well. After the medication has been administered, the media is removed, and cells are fixed for 30 minutes at 4°C in cold 10% trichloroacetic acid. Following a water wash, the cells are stained for 30 min at room temperature with 0.4% SRB and then again washed with 1% acetic acid. Finally, the stain is solubilized for 30 min at room temperature with 10 mM tris. A plate reader is used to measure the absorbance at 565 nm. The raw absorbance (OD) data are used to create cell proliferation curves. Version 5.00 of GraphPad Prism is used for statistical analysis and data visualization[2].
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| Animal Protocol |
Mice: Five to six-week-old female athymic nude mice are used. Using Trypsin-EDTA, cells from mid-log phase cultures are harvested to create A375 human melanoma xenograft tumors. The right flank of 6–8-week-old mice is injected subcutaneously with approximately 5×106 cells suspended in Hanks' balanced salt solution (HBSS). When all of the mice in an experiment have tumors that are between 100 and 200 mm3 in size for antitumor efficacy studies and between 300 and 500 mm3 in size for pharmacodynamic (PD) studies, TAK-733 (1 mg/kg or 10 mg/kg) is started orally[2].
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| References |
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| Molecular Formula |
C17H15F2IN4O4
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| Molecular Weight |
504.23
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| Exact Mass |
504.01
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| Elemental Analysis |
C, 40.49; H, 3.00; F, 7.54; I, 25.17; N, 11.11; O, 12.69
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| CAS # |
1035555-63-5
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| Related CAS # |
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| Appearance |
White to off-white solid powder
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| SMILES |
CN1C2=C(C(=C(C1=O)F)NC3=C(C=C(C=C3)I)F)C(=O)N(C=N2)C[C@H](CO)O
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| InChi Key |
RCLQNICOARASSR-SECBINFHSA-N
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| InChi Code |
InChI=1S/C17H15F2IN4O4/c1-23-15-12(16(27)24(7-21-15)5-9(26)6-25)14(13(19)17(23)28)22-11-3-2-8(20)4-10(11)18/h2-4,7,9,22,25-26H,5-6H2,1H3/t9-/m1/s1
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| Chemical Name |
3-[(2R)-2,3-dihydroxypropyl]-6-fluoro-5-(2-fluoro-4-iodoanilino)-8-methylpyrido[2,3-d]pyrimidine-4,7-dione
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| Synonyms |
TAK 733; TAK733; TAK-733
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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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| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9832 mL | 9.9161 mL | 19.8322 mL | |
| 5 mM | 0.3966 mL | 1.9832 mL | 3.9664 mL | |
| 10 mM | 0.1983 mL | 0.9916 mL | 1.9832 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 |
| NCT00948467 | Completed | Drug: TAK-733 | Advanced Metastatic Melanoma Advanced Non-hematologic Malignancies |
Millennium Pharmaceuticals, Inc. |
December 2009 | Phase 1 |
| NCT01613261 | Withdrawn | Drug: TAK-733 and alisertib | Advanced Nonhematologic Malignancies |
Millennium Pharmaceuticals, Inc. |
August 2013 | Phase 1 |
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Pharmacokinetic and pharmacodynamic effects of TAK-733 in A375 tumor-bearing mice following oral administration of (A) 1 mg/kg or (B) 10 mg/kg dose. A375 tumor cells were implanted subcutaneously in the flank of nu/nu mice (3/time point). Administration was initiated when all mice had tumors ranging in size from 300 to 500 mm3(Day 10). TAK-733 was given as a single oral dose.Mol Cancer Ther.2015 Feb;14(2):317-25. |
Effects of TAK-733 on growth of A375 melanoma tumor xenografts in athymic nude mice. A375 melanoma cells were implanted subcutaneously in the flank of nu/nu mice (5/group). Administration was initiated 10 days after the tumor implant, when all mice had tumors ranging in size from 80 to 225 mm3(Day 10). TAK-733 was given orally daily for 14 days (QD 1-14) or 3 days per week for 2 cycles (M, TH, SAT ×2).Mol Cancer Ther.2015 Feb;14(2):317-25. |
Tumor regrowth kinetics for PDTX model MB1374 administered with vehicle or TAK-733 (10 mg/kg). Inset, original tumor growth inhibition study for 30 days. Red lines indicate TAK-733 administration times, black lines indicate cessation of TAK-733 for tumor regrowth periods.Mol Cancer Ther.2015 Feb;14(2):317-25. |
Antiproliferative effects of TAK-733 against a panel of human cutaneous melanoma cell lines. Cell lines were treated with increasing doses of TAK-733 for 72 hours and proliferation was assessed using the SRB assay. IC50values are depicted. BRAF and NRAS mutational status in depicted in the table below.Mol Cancer Ther.2015 Feb;14(2):317-25. |
Immunoblot analysis of downstream effectors upon administration of TAK-733. A375 and RPMI 7951 cell lines were serum starved overnight and then administered TAK-733 for 1 hr. Cells were then challenged with 10% FBS for 30 mins, harvested and immunoblotted with the indicated antibodies.Mol Cancer Ther.2015 Feb;14(2):317-25. |
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