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Purity: ≥98%
TAK-243 (also known as MLN-7243; TAK243; AOB-87172) is a novel, potent and selective inhibitor of ubiquitin-like modifier activating enzyme 1 (UBA1; also named as ubiquitin-activating enzyme (UAE)) with potential anticancer activity. TAK-243 binds to and inhibits UAE, which prevents both protein ubiquitination and subsequent protein degradation by the proteasome. This results in an excess of proteins in the cells and may lead to endoplasmic reticulum (ER) stress-mediated apoptosis. This inhibits tumor cell proliferation and survival.
| Targets |
UBA1(IC50= 1 nM)
|
|---|---|
| ln Vitro |
With varying EC50 values ranging from 0.006 μM to 1.31 μM, TAK-243 exhibits anti-proliferative effect on a panel of cell lines derived from hematologic and solid tumors[1].
Human AML cell lines (OCI-AML2, TEX, U937, and NB4) exhibit reduced growth and viability in response to TAK-243 in a concentration- and time-dependent manner, with IC50s ranging from 15 to 40 nM after 48 hours of treatment[3]. |
| ln Vivo |
No toxicity was observed in mice (T/C=0.02) as TAK-243 significantly delays the growth of tumors without affecting body weight, serum chemistry, or organ histology. In both tested samples, TAK-243 lessens the primary AML tumor burden without causing any toxicity[3].
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| Cell Assay |
Normal keratinocytes, such as recessive dystrophic epidermolysis bullosa keratinocytes (RDEBK) and normal human keratinocytes (NHK), as well as cSCC cell lines, are seeded into 96-well plates. The CellTox Green Cytotoxicity Assay is used to analyze live cell number and cell death using an IncuCyte ZOOM real-time imager. One tool used to calculate relative EC50 values is GraphPad Prism. In clonogenic assays, six-well plates are seeded with cells. After adding inhibitors (such as TAK-243; 0.01, 0.1, 1, and 10 μM) for the specified durations, cells are kept in drug-free medium for a maximum of two weeks to enable colony formation. Colonies are stained with crystal violet after being fixed in 10% methanol and 10% acetic acid[1].
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| Animal Protocol |
Mice[2]
TAK-243's preclinical effectiveness and toxicity are evaluated using AML mouse models. SCID mice are given subcutaneous (sc) injections of OCI-AML2 cells, and TAK-243 (20 mg/kg sc twice weekly) is administered to the mice once tumors are palpable. In an extra model, NOD-SCID mice are given injections of primary AML cells from two patients into their femurs. Mice are administered TAK-243 (20 mg/kg sc twice weekly) two weeks post-injection. Following three weeks of therapy, the mice are killed, and flow cytometry is used to quantify the amount of AML engraftment in the non-injected femur[2]. |
| References |
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| Additional Infomation |
TAK-243 is under investigation in clinical trial NCT03816319 (TAK-243 in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia or Refractory Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia).
UAE Inhibitor TAK-243 is a small molecule inhibitor of ubiquitin-activating enzyme (UAE), with potential antineoplastic activity. UAE inhibitor TAK-243 binds to and inhibits UAE, which prevents both protein ubiquitination and subsequent protein degradation by the proteasome. This results in an excess of proteins in the cells and may lead to endoplasmic reticulum (ER) stress-mediated apoptosis. This inhibits tumor cell proliferation and survival. UAE, also called ubiquitin E1 enzyme (UBA1; E1), is more active in cancer cells than in normal, healthy cells. |
| Molecular Formula |
C19H20F3N5O5S2
|
|---|---|
| Molecular Weight |
519.517811775208
|
| Exact Mass |
519.085
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| Elemental Analysis |
C, 43.93; H, 3.88; F, 10.97; N, 13.48; O, 15.40; S, 12.34
|
| CAS # |
1450833-55-2
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| PubChem CID |
71715374
|
| Appearance |
White to off-white crystalline solid
|
| Density |
1.8±0.1 g/cm3
|
| Index of Refraction |
1.712
|
| LogP |
1.49
|
| Hydrogen Bond Donor Count |
4
|
| Hydrogen Bond Acceptor Count |
13
|
| Rotatable Bond Count |
7
|
| Heavy Atom Count |
34
|
| Complexity |
804
|
| Defined Atom Stereocenter Count |
4
|
| SMILES |
S(=O)(=O)(OC[C@@H]1[C@@H](O)[C@@H](O)[C@H](NC2=CC=NC3N2N=C(C=3)C2C=C(SC(F)(F)F)C=CC=2)C1)N
|
| InChi Key |
PUMGWJMQPGYZFC-IDCJVQTKSA-N
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| InChi Code |
InChI=1S/C19H20F3N5O5S2/c1-32-34(30,31)26-14-8-13(17(28)18(14)29)24-15-5-6-23-16-9-12(25-27(15)16)10-3-2-4-11(7-10)33-19(20,21)22/h2-7,9,13-14,17-18,24,26,28-29H,8H2,1H3/t13-,14+,17+,18-/m1/s1
|
| Chemical Name |
methyl ((1S,2R,3S,4R)-2,3-dihydroxy-4-((2-(3-((trifluoromethyl)thio)phenyl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)cyclopentyl)sulfamate
|
| Synonyms |
TAK-243; TAK 243; TAK243; MLN7243; MLN-7243; MLN 7243; AOB87172; AOB-87172; AOB 87172
|
| 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 |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
|
| Solubility (In Vitro) |
DMSO : 50~100 mg/mL ( 96.24~192.48 mM )
Ethanol : ~25 mg/mL Water : ~1 mg/mL (~1.92 mM ) |
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.00 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 20.8 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: ≥ 2.08 mg/mL (4.00 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 20.8 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: ≥ 2.08 mg/mL (4.00 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 5% DMSO + 40% PEG300 + 5% Tween80 + 50% ddH2O: 5mg/ml |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9249 mL | 9.6243 mL | 19.2485 mL | |
| 5 mM | 0.3850 mL | 1.9249 mL | 3.8497 mL | |
| 10 mM | 0.1925 mL | 0.9624 mL | 1.9249 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 |
| NCT03816319 | Not yet recruiting | Drug: UAE Inhibitor TAK-243 | Myelodysplastic Syndrome Recurrent Acute Myeloid Leukemia |
National Cancer Institute (NCI) |
November 6, 2023 | Phase 1 |
| NCT02045095 | Terminated | Drug: MLN7243 | Advanced Malignant Solid Tumors | Millennium Pharmaceuticals Inc |
January 31, 2014 | Phase 1 |
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