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Purity: ≥98%
ENMD-2076 Tartrate, the tartrate salt of ENMD-981693 (MKC-1693), is a novel, potent and orally bioactive multi-kinase inhibitor with potential antineoplastic activity. With IC50 values of 14 nM and 1.86 nM, it suppresses Aurora A and Flt3, exhibiting a 25-fold preference for Aurora A over Aurora B. ENMD-2076 exhibits strong in vivo antitumor efficacy as well as strong anti-proliferative activity in vitro.
| Targets |
Aurora A (IC50 = 1.86 nM); KDR (IC50 = 58.2 nM); Flt-4 (IC50 = 15.9 nM); FGFR1 (IC50 = 92.7 nM); FGFR2 (IC50 = 70.8 nM); PDGFRα (IC50 = 56.4 nM); Flt3 (IC50 = 14 nM)
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| ln Vitro |
ENMD-2076 is selective for Aurora A than for Aurora B (IC50=350 nM). HUVEC growth is inhibited by ENMD-2076 at an IC50 of 0.15 mM. The IC50 values range from 0.025 to 0.53 mM against ten human leukemia cell lines. The most sensitive cells in this panel by a factor bigger than four are MV4:11 cells. ENMD-2076 treatment of the lymphoma-derived U937 cell line results in a dose-dependent increase in both the induction of apoptosis and G2-M-phase arrest. In THP-1 cells, which have been demonstrated to express FL-responsive wild-type Flt-3 (18), ENMD-2076 inhibits Flt3 autophosphorylation induced by cellular Flt3 ligand (FL) at an IC50 value of 28 nM. For MO7e cells, ENMD-2076 has an IC50 value of 40 nM, which inhibits the autophosphorylation of Kit induced by stem cell factor (SCF). The IC50 value of ENMD-2076 is 7 nM, which is sufficient to inhibit VEGFR2/KDR autophosphorylation.
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| ln Vivo |
ENMD-2076 treatment causes tumor growth or regression to be statistically significantly inhibited in a dose-dependent manner. Furthermore, while slow-growing (like A375 melanoma) and fast-growing (like HT29 colon carcinoma) tumors are both inhibited by ENMD-2076, there is no correlation between the rate of tumor growth and the antitumor efficacy, which is theoretically expected for a mitotic kinase inhibitor. With the exception of the A375 model, studies have not found any weight loss or indications of morbidity at daily doses of up to 302 mg/kg (equivalent to 200 mg/kg of the free base) for ENMD-2076.
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| Enzyme Assay |
Recombinant Aurora A and B kinase enzyme assays are conducted in kinase assay buffer, which is supplemented with 2 mM of DTT and contains 50 mM of HEPES, pH 7.5, 10 mM of MgCl2, 5 mM of EGTA, and 0.05% Brij-35. The enzyme concentration that causes the peptide substrate to phosphorylate by about 30% after an hour and the ATP concentration that corresponds to each enzyme's apparent Km are used to calculate activities. Grafit is used to plot relative enzyme activity versus ENMD-2076 concentration on dose-response curves, which are then used to determine IC50 values[1].
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| Cell Assay |
In a 96-well plate, 500 cells are plated per well, and the compound is incubated with 9 doses (ranging from 0.3 nM to 125 mM) for 96 hours to determine the antiproliferative effect on adherent tumor cell lines. Using the sulforhodamine B assay, cellular proliferation is quantified[1].
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| Animal Protocol |
Mice: In 5- to 6-week-old CB.17 SCID or NCr nude mice, cell lines are injected subcutaneously or into the mammary fat pad (MDA-MB-231 only). Before receiving medication, tumors are left to grow for a period of 10 to 50 days. ENMD-2076 in water or ENMD-2076 free base in CMC-Tween vehicle (0.085% Tween 80 in water and 0.075% carboxymethylcellulose) is used orally for all treatments. One computes the percent inhibition of tumor growth[1].
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| References |
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| Additional Infomation |
Aurora A Kinase/Tyrosine Kinase Inhibitor ENMD-2076 is an orally bioavailable synthetic small molecule with potential antiangiogenic and antineoplastic activities. Aurora A kinase/tyrosine kinase inhibitor ENMD-2076 selectively binds to and inhibits non-specified tyrosine kinases and Aurora kinases (AKs). The inhibition of AKs may result in the inhibition of cell division and proliferation and may induce apoptosis in tumor cells that overexpress AKs; antiangiogenic activity is related to the inhibition of angiogenic tyrosine kinases. AKs are serine-threonine kinases that play an essential role in mitotic checkpoint control during mitosis and are important regulators of cell division and proliferation.
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| Molecular Formula |
C25H31N7O6
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| Molecular Weight |
525.56
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| Exact Mass |
525.233
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| CAS # |
1291074-87-7
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| Related CAS # |
ENMD-2076;934353-76-1
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| PubChem CID |
16041424
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| Appearance |
Light brown to khaki solid
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| LogP |
0.476
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
28
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| Complexity |
499
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O[C@H](C(O)=O)[C@@H](C(O)=O)O.CC1=CC(NC2=NC(/C=C/C3=CC=CC=C3)=NC(N4CCN(CC4)C)=C2)=NN1
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| InChi Key |
KGWWHPZQLVVAPT-PCWHHUEVSA-N
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| InChi Code |
InChI=1S/C21H25N7.C4H6O6/c1-16-14-20(26-25-16)23-19-15-21(28-12-10-27(2)11-13-28)24-18(22-19)9-8-17-6-4-3-5-7-17;5-1(3(7)8)2(6)4(9)10/h3-9,14-15H,10-13H2,1-2H3,(H2,22,23,24,25,26);1-2,5-6H,(H,7,8)(H,9,10)/b9-8+;/t;1-,2-/m.0/s1
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| Chemical Name |
(2S,3S)-2,3-dihydroxybutanedioic acid;6-(4-methylpiperazin-1-yl)-N-(5-methyl-1H-pyrazol-3-yl)-2-[(E)-2-phenylethenyl]pyrimidin-4-amine
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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, 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) |
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| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9027 mL | 9.5137 mL | 19.0273 mL | |
| 5 mM | 0.3805 mL | 1.9027 mL | 3.8055 mL | |
| 10 mM | 0.1903 mL | 0.9514 mL | 1.9027 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.
Antiangiogenic action of ENMD-2076. Mol Cancer Ther. 2011 Jan;10(1):126-37. |
ENMD-2076 inhibits Flt3, VEGFR2/KDR, FGFR-1/2, and Aurora A in vivo. Mol Cancer Ther. 2011 Jan;10(1):126-37. |
ENMD-2076 inhibits blood vessel formation and impacts the growth of established MDA-MB-231 tumors. Mol Cancer Ther. 2011 Jan;10(1):126-37. |
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