A multi-kinase inhibitor
ENMD-2076 is a selective inhibitor of Aurora A and Flt3 with IC50 value of 14 and 1.86 nM[1].
Aurora kinases contains aurora A, aurora B and aurora C. They are serine/threonine kinases witch play an important role in cell proliferation. Aurora kinases are essential for cellular division by controlling segregation of chromatid. Aurora A is required for correct function of the centrosomes during the prophase of mitosis [1]. VEGFR (VEGF receptors) are receptors for VEGF (vascular endothelial growth factor). There are VEGFR 1, 2 and 3 which three main subtypes of VEGFR. The VEGFRs are tyrosine kinase receptors which are activited by binding to VEGFs then mediate the cellular responses to VEGF including the formation of the circulatory system (vasculogenesis) and the growth of blood vessels(angiogenesis) [1].
ENMD-2076 indicates activities of RET, FLT3, FLT4/VEGFR3, SRC, CSF1R/FMS, NTRK1, FGFR1/2, VEGFR2/KDR, LCK, and PDGFRα which all are kinases involved in angiogenes with IC50 from 1.86-120 nM. ENMD-2076 can inhibit the growth of hematopoietic cancer cell lines and lots of solid tumor with IC50 values from 25 to 700 nM in vitro[1]. ENMD-2076 significantly caused cytotoxicity in multiple myeloma (MM) cell lines and primary cells. ENMD-2076 also inhibited the phosphoinositide 3-kinase (PI3K)/AKT pathway. ENMD-2076 also induced cell cycle arrest in G2/M phase by inhibiting the activities of aurora kinases containing A and B class.[2]
ENMD-2076 regresses formed vessels and prevents new blood vessels formation in tumorxenograft models. [1] ENMD-2076 resulted in inhibition of tumour growth with oral treatment a dose-dependent manner with 50, 100, 200 mg/kg per day with human plasmacytoma xenografts[2].
参考文献:
[1].? Fletcher GC, Brokx RD, Denny TA, Hembrough TA, Plum SM, Fogler WE, Sidor CF, Bray MR: ENMD-2076 is an orally active kinase inhibitor with antiangiogenic and antiproliferative mechanisms of action. Mol Cancer Ther 2011, 10(1):126-137.
[2].? Wang X, Sinn AL, Pollok K, Sandusky G, Zhang S, Chen L, Liang J, Crean CD, Suvannasankha A, Abonour R et al: Preclinical activity of a novel multiple tyrosine kinase and aurora kinase inhibitor, ENMD-2076, against multiple myeloma. Br J Haematol 2010, 150(3):313-325.
| Cell experiment [1]: | |
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Cell lines |
HUVECs |
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Preparation method |
The solubility of this compound in DMSO is > 18.8 mg/mL. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below - 20 °C for several months. |
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Reacting condition |
0 ~ 139 nM |
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Applications |
In HUVECs, ENMD-2076 inhibited VEGFR2/KDR autophosphorylation, with an IC50 value of 7 nM. Moreover, ENMD-2076 also inhibited FGFR activity, with an IC50 value of 600 nM. In addition, ENMD-2076 inhibited VEGF- and FGF-stimulated HUVEC cell proliferation, with the IC50 values of 76 nM and 139 nM, respectively. |
| Animal experiment [1]: | |
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Animal models |
Nude mice bearing multiple cancer cell line xenografts |
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Dosage form |
25 ~ 302 mg/kg; p.o. |
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Applications |
In nude mice bearing multiple cancer cell line xenografts, ENMD-2076 significantly and dose-dependently inhibited tumor growth. Moreover, ENMD-2076 similarly inhibited fast-growing (e.g. A375 melanoma) and slow-growing (e.g. HT29 colon carcinoma) tumors. In addition, ENMD-2076 was well tolerated up to 302 mg/kg/day, without weight loss or sign of morbidity, except for the A375 model. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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参考文献: [1]. Fletcher GC, Brokx RD, Denny TA, Hembrough TA, Plum SM, Fogler WE, Sidor CF, Bray MR: ENMD-2076 is an orally active kinase inhibitor with antiangiogenic and antiproliferative mechanisms of action. Mol Cancer Ther 2011, 10(1):126-137. | |
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