ENMD-2076

Catalog No.S1181

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 VEGFR2/KDR and VEGFR3, FGFR1 and FGFR2 and PDGFRα. Phase 2.

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ENMD-2076 Chemical Structure

ENMD-2076 Chemical Structure
Molecular Weight: 375.47

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Product Information

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Product Description

Biological Activity

Description 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 VEGFR2/KDR and VEGFR3, FGFR1 and FGFR2 and PDGFRα. Phase 2.
Targets FLT3 [1] RET [1] Aurora A [2] VEGFR3/FLT4 [1]

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IC50 1.86 nM 10.4 nM 14 nM 15.9 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 PDGFRα 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 μM, 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 μM, 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]
Features Multi-target, anti-proliferative, pro-apoptotic activity, anti-angiogenic.

Protocol(Only for Reference)

Kinase Assay: [1]

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. Dose–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 μM if the apparent Km could not be reached. Percent inhibition is determined at an ENMD-2076 free base concentration of 1 μM; for kinases where significant inhibition is noted, IC50 values are determined by generating full 10-point dose–response curves.

Cell Assay: [1]

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
Concentrations 0.3 nM - 125 μM
Incubation Time 48 or 96 hours
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 5 × 103 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-

Animal Study: [1]

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.
Formulation ENMD-2076 in water or ENMD-2076 free base in CMC-Tween vehicle (0.075% carboxymethylcellulose, 0.085% Tween 80 in water)
Dosages ~300 mg/kg
Administration Administered orally

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDog
Weight (kg)0.020.151.80.40.0810
Body Surface Area (m2)0.0070.0250.150.050.020.5
Km factor36128520
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.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Fletcher GC, et al, Mol Cancer Ther, 2011, 10(1), 126-137.

[2] Wang X, et al. Br J Haematol, 2010, 150(3), 313-325.

Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2016-07-30)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT02234986 Recruiting Advanced Adult Hepatocellular Carcinoma|Advanced Fibrolamellar Carcinoma CASI Pharmaceuticals, Inc. October 2015 Phase 2
NCT01914510 Recruiting Ovarian Clear Cell Carcinoma University Health Network, Toronto September 2013 Phase 2
NCT01719744 Completed Advanced|Metastatic|Soft Tissue Sarcoma University Health Network, Toronto January 2013 Phase 2
NCT01639248 Recruiting Triple Negative Breast Cancer CASI Pharmaceuticals, Inc.|University of Colorado, Denver  ...more CASI Pharmaceuticals, Inc.|University of Colorado, Denver|Indiana University Melvin and Bren Simon Cancer Center July 2012 Phase 2
NCT01104675 Completed Ovarian Cancer|Fallopian Cancer|Peritoneal Cancer CASI Pharmaceuticals, Inc. April 2010 Phase 2

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Chemical Information

Download ENMD-2076 SDF
Molecular Weight (MW) 375.47
Formula

C21H25N7

CAS No. 934353-76-1
Storage 3 years -20℃powder
6 months-80℃in solvent
Synonyms N/A
Solubility (25°C) * In vitro DMSO 105 mg/mL (279.64 mM)
Water 1 mg/mL (2.66 mM)
Ethanol <1 mg/mL (<1 mM)
In vivo 0.5% CMC+0.25% Tween 80 30 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Name (E)-N-(5-methyl-1H-pyrazol-3-yl)-6-(4-methylpiperazin-1-yl)-2-styrylpyrimidin-4-amine

Tech Support

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