ENMD-2076 is an orally-active, Aurora A/angiogenic kinase inhibitor with a unique kinase selectivity profile and multiple mechanisms of action. ENMD-2076 has been shown to inhibit a distinct profile of angiogenic tyrosine kinase targets in addition to the Aurora A kinase. ENMD-2076 also targets the VEGFR, Flt-3 and FGFR3 kinases which have been shown to play important roles in the pathology of several cancers. ENMD-2076 has shown promising activity in Phase 1 clinical trials in solid tumor cancers, leukemia, and multiple myeloma. ENMD-2076 is currently in a Phase 2 trial for ovarian cancer, and preclinical and clinical activities are ongoing in assessing the compound's applicability for other forms of cancer.
|Cell lines||solid tumor cell lines and HUVECs, human leukemia cell lines|
|Preparation method||Cell and proliferative assays
Cell lines were routinely tested for mycoplasma and used at low passage numbers (<10). The antiproliferative effect of ENMD-2076 on adherent tumor cell lines was measured by plating 500 cells per well in a 96-well plate and incubating with 9 doses of compound, spanning 0.3 nmol/L to 125 μmol/L, for 96 hours. Cellular proliferation was measured using the sulforhodamine B (SRB; Sigma Aldrich) assay (10). The leukemia-derived, nonadherent cell lines were assayed by plating 5,000 cells per well in a 96-well plate. The cells were incubated with 9 doses of compound, spanning 0.3 nmol/L to 125 μmol/L, for 48 hours and then survival was assayed using the Alamar Blue reagent (Invitrogen) according to the manufacturer’s instructions. To measure the effect of ENMD-2076 on VEGF- and fibroblast growth factor (FGF)-induced proliferation of human umbilical vein endothelial cell (HUVEC), cells were serum starved for 6 hours, then treated with ENMD-2076 free base, and stimulated with 5 ng/mL bFGF or 25 ng/mL VEGF (R and D Systems) for 72 hours. Cell proliferation was measured using WST-1 (Roche Applied Science) according to the manufacturer’s instructions.
|Concentrations||0.3 nM~125 μM|
|Incubation time||48 or 96 h|
|Animal models||MDA-MB-231 tumor xenograft model of 5- to 6-week-old CB.17 SCID or NCr nude mice|
|Formulation||ENMD-2076 in water or ENMD-2076 free base in CMC-Tween vehicle (0.075% carboxymethylcellulose, 0.085% Tween 80 in water)|
|Dosages||75 or 302 mg/kg daily|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
ENMD-2076, an oral inhibitor of angiogenic and proliferation kinases, has activity in recurrent, platinum resistant ovarian cancer.
Matulonis et al. Eur J Cancer. 2012 Aug 21. PMID: 22921155.
ENMD-2076 for hematological malignancies.
How et al. Expert Opin Investig Drugs. 2012 May;21(5):717-32. PMID: 22397360.
From cell biology to therapy: ENMD-2076 in the treatment of multiple myeloma.
Zhang et al. Expert Opin Investig Drugs. 2011 Jul;20(7):1015-28. PMID: 21615212.
ENMD-2076 is an orally active kinase inhibitor with antiangiogenic and antiproliferative mechanisms of action.
Fletcher et al. Mol Cancer Ther. 2011 Jan;10(1):126-37. PMID: 21177375.
Phase I safety, pharmacokinetic, and pharmacodynamic study of ENMD-2076, a novel angiogenic and Aurora kinase inhibitor, in patients with advanced solid tumors.
Diamond et al. Clin Cancer Res. 2011 Feb 15;17(4):849-60. PMID: 21131552.
Preclinical activity of a novel multiple tyrosine kinase and aurora kinase inhibitor, ENMD-2076, against multiple myeloma.
Wang et al. Br J Haematol. 2010 Aug;150(3):313-25. PMID: 20560971.
Assessment of the in vivo antitumor effects of ENMD-2076, a novel multitargeted kinase inhibitor, against primary and cell line-derived human colorectal cancer xenograft models.
Tentler et al. Clin Cancer Res. 2010 Jun 1;16(11):2989-98. PMID: 20406842.
|Related Aurora Kinase Products|
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GSK1070916 is a reversible and ATP-competitive inhibitor of Aurora B/C with IC50 of 3.5 nM/6.5 nM. It displays >100-fold selectivity against the closely related Aurora A-TPX2 complex.
PHA-680632 is potent inhibitor of Aurora A, Aurora B and Aurora C with IC50 of 27 nM, 135 nM and 120 nM, respectively. It has 10- to 200-fold higher IC50 for FGFR1, FLT3, LCK, PLK1, STLK2, and VEGFR2/3.
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PF-03814735 is a novel, potent and reversible inhibitor of Aurora A/B with IC50of 0.8 nM/5 nM, is less potent to Flt3, FAK, TrkA, and minimally active to Met and FGFR1.
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