ENMD-2076

ArtNr	S1181-10000
Hersteller	Selleckchem
CAS-Nr.	934353-76-1
Menge	10 g
Quantity options	10 mg 1 g 10 g 10 mM/1 mL 200 mg 5 mg 50 mg 5 g
Kategorie	Oncology Neuroscience Molecular Targets for Neuroscience Inhibitors & Compound Libraries Small Molecules By Organ Skin Cancer Colorectal Cancer Breast Cancer Heart & Blood Cancer Lymphatic System Cancer Bone Cancer
Typ	Inhibitors
Specific against	other
Smiles	CC1=CC(=NN1)NC2=CC(=NC(=N2)C=CC3=CC=CC=C3)N4CCN(CC4)C
ECLASS 10.1	32160490
ECLASS 11.0	32160490
UNSPSC	12000000
Alias	934353-76-1'
Similar products	ENMD-2076
Lieferbar
Manufacturer - Targets	FLT4, FLT3
Storage Conditions	2 years -80 in solvent
Molecular Weight	525, 56
Administration	Administered orally
Animal Models	Tumor models including HCT-116, HT29, CT-26, A375, MDA-MB-231, H929, OPM-2, MV4, 11 and HL60 are established in CB.17 SCID or NCr nude mice.
Cell lines	Human leukemia cell lines including MV4, 11, U937, Kasumi, MO7e, HL-60, TF-1, Jurkat, K562, THP-1, Hel 92.1.7, Solid tumor cell lines and HUVEC including PANC-1, HCT116, A549, HT-29, MCF7, PC-3, BXPC-3 and HUVEC
Clinical Trials	ENMD-2076 is currently in Phase I clinical trials in patients with relapsed or refractory multiple myeloma.
Concentrations	0.3 nM - 125 uM
Dosages	ca.300 mg/kg
Formulation	ENMD-2076 in water or ENMD-2076 free base in CMC-Tween vehicle (0.075% carboxymethylcellulose, 0.085% Tween 80 in water)
IC50	14 nM, 14 nM, 14 nM, 14 nM, 14 nM, 14 nM
In vitro	ENMD-2076 indicates activity against multiple kinases involved in angiogenesis, including FLT3, RET, FLT4/VEGFR3, SRC, NTRK1, CSF1R/FMS, LCK, VEGFR2/KDR, FGFR1/2, and PDGFRalpha with IC50 from 1.86-120 nM. ENMD-2076 inhibits the growth of a wide range of human solid tumor and hematopoietic cancer cell lines with IC50 from 0.025 to 0.7 uM, which induces apoptosis and G2/M phase arrest. ENMD-2076 induces regression or complete inhibition of tumor growth in tumor xenograft models derived from breast, colon, melanoma, leukemia, and multiple myeloma cell lines. [1] ENMD-2076 is the L (+) tartrate salt of ENMD-981693. ENMD-2076 shows significant cytotoxicity against myeloma cell lines (IM9, ARH-77, U266, RPMI 8226, MM.1S, MM.1R, NCI-H929) and primary cells with IC50 from 2.99 to 7.06 uM, which induces apoptosis. ENMD-2076 indicates low cytotoxicity to haematopoietic progenitors. ENMD-2076 inhibits the phosphoinositide 3-kinase/Akt pathway and downregulates survivin and X-linked inhibitor of apoptosis. ENMD-2076 also inhibits aurora A and B kinases, and induces G2/M cell cycle arrest. [2]
In vivo	ENMD-2076 has sustained inhibitory effects on the activation of Flt3 as well as VEGFR2/KDR and FGFR1/2 in HT29 xenograft model. ENMD-2076 could prevent the formation of new blood vessels and regress formed vessels in MDA-MB-231 xenograft model. [1] Oral treatment with ENMD-2076 (50, 100, 200 mg/kg per day) inhibits the tumour growth in H929 human plasmacytoma xenografts, with significant reduction in phospho-Histone 3 (pH3), Ki-67, and angiogenesis, and also a significant increase in cleaved caspase-3. [2]
Incubation Time	48 or 96 hours
Kinase Assay	Kinase assays, Recombinant Aurora A and B kinase enzymes and appropriate PanVera Z'-Lyte kinase assay kits are purchased. Assays are carried out in kinase assay buffer (50 mM of HEPES, pH 7.5, 10 mM of MgCl2, 5 mM of EGTA, 0.05% Brij-35) supplemented with 2 mM of DTT. Activities are determined at an ATP concentration equivalent to the apparent Km for each enzyme, and an enzyme concentration that results in approximately 30% phosphorylation of the peptide substrate after 1 hour. Doseâ€“response curves of relative enzyme activity versus ENMD-2076 concentration are plotted with Grafit and used to calculate IC50 values. Potency of ENMD-2076 free base against a select panel of 100 kinase enzymes is determined using the SelectScreen kinase profiling service. ATP concentrations are at the apparent Km for each enzyme or 100 uM if the apparent Km could not be reached. Percent inhibition is determined at an ENMD-2076 free base concentration of 1 uM, for kinases where significant inhibition is noted, IC50 values are dermined by generating full 10-point doseâ€“response curves.
Method	The antiproliferative effect of ENMD-2076 on adherent tumor cell lines is measured by plating 500 cells per well in a 96-well plate and incubating with ENMD-2076 for 96 hours. Cellular proliferation is measured using the sulforhodamine B assay. The leukemia-derived, nonadherent cell lines are assayed by plating 5x103 cells per well in a 96-well plate. The cells are incubated with ENMD-2076 for 48 hours and then survival is assayed using the Alamar Blue reagent. To measure the effect of ENMD-2076 on VEGF- and fibroblast growth factor (FGF)-induced proliferation of human umbilical vein endothelial cell (HUVEC), cells are 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 is measured using WST-1.
Solubility (25C)	DMSO 105 mg/mL, Water 1 mg/mL, Ethanol <1 mg/mL
Information	ENMD-2076 has selective activity against Aurora A and Flt3 with IC50 of 14 nM and 1.86 nM, 25-fold selective for Aurora A than over Aurora B and less potent to RET, SRC, NTRK1/TRKA, CSF1R/FMS, VEGFR2/KDR, FGFR and PDGFRα. ENMD-2076 inhibits the growth of a wide range of human solid tumor and hematopoietic cancer cell lines with IC50 from 0.025 to 0.7 μM, which induces apoptosis and G2/M phase arrest. Phase 2.
Chemical Name	(E)-N-(5-methyl-1H-pyrazol-3-yl)-6-(4-methylpiperazin-1-yl)-2-styrylpyrimidin-4-amine
Features	Multi-target, anti-proliferative, pro-apoptotic activity, anti-angiogenic

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