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1291074-87-7 molecular structure
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(2R,3R)-2,3-dihydroxybutanedioic acid; N-(5-methyl-1H-pyrazol-3-yl)-6-(4-methylpiperazin-1-yl)-2-[(E)-2-phenylethenyl]pyrimidin-4-amine

ChemBase ID: 72564
Molecular Formular: C25H31N7O6
Molecular Mass: 525.55694
Monoisotopic Mass: 525.23358175
SMILES and InChIs

SMILES:
n1c(cc([nH]1)C)Nc1cc(nc(n1)/C=C/c1ccccc1)N1CCN(CC1)C.OC(=O)[C@@H]([C@H](C(=O)O)O)O
Canonical SMILES:
OC(=O)[C@@H]([C@H](C(=O)O)O)O.CN1CCN(CC1)c1nc(/C=C/c2ccccc2)nc(c1)Nc1n[nH]c(c1)C
InChI:
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.1/s1
InChIKey:
KGWWHPZQLVVAPT-STTJLUEPSA-N

Cite this record

CBID:72564 http://www.chembase.cn/molecule-72564.html

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NAMES AND DATABASE IDS

NAMES AND DATABASE IDS

Names Database IDs
IUPAC name
(2R,3R)-2,3-dihydroxybutanedioic acid; N-(5-methyl-1H-pyrazol-3-yl)-6-(4-methylpiperazin-1-yl)-2-[(E)-2-phenylethenyl]pyrimidin-4-amine
IUPAC Traditional name
L-tartaric acid; N-(5-methyl-1H-pyrazol-3-yl)-6-(4-methylpiperazin-1-yl)-2-[(E)-2-phenylethenyl]pyrimidin-4-amine
Synonyms
ENMD-981693
ENMD-2076
CAS Number
1291074-87-7
PubChem SID
162037489
PubChem CID
24776050

DATA SOURCES

DATA SOURCES

All Sources Commercial Sources Non-commercial Sources
Data Source Data ID Price
Selleck Chemicals
S1181 external link Add to cart Please log in.
Data Source Data ID
PubChem 24776050 external link

CALCULATED PROPERTIES

CALCULATED PROPERTIES

JChem
Acid pKa 12.222443  H Acceptors
H Donor LogD (pH = 5.5) 2.8036532 
LogD (pH = 7.4) 4.555973  Log P 4.8288617 
Molar Refractivity 116.5054 cm3 Polarizability 42.15887 Å3
Polar Surface Area 72.97 Å2 Rotatable Bonds
Lipinski's Rule of Five false 

PROPERTIES

PROPERTIES

Physical Property Safety Information Pharmacology Properties Product Information Bioassay(PubChem)
Solubility
DMSO expand Show data source
Storage Condition
-20°C expand Show data source
Target
Aurora Kinase expand Show data source
Flt expand Show data source
Salt Data
Free Base expand Show data source

DETAILS

DETAILS

Selleck Chemicals Selleck Chemicals
Selleck Chemicals - S1181 external link
Research Area
Description Ovarian cancer,Multiple myeloma, Cancer
Biological Activity
Description ENMD-2076 is a selective inhibitor of Aurora A and Aurora B with IC50 of 14 nM and 350 nM, respectively.
Targets Aurora A Aurora B
IC50 14 nM 350 nM [1]
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]
Clinical Trials ENMD-2076 is currently in Phase I clinical trials in patients with relapsed or refractory multiple myeloma.
Features Multi-target, anti-proliferative, pro-apoptotic activity, anti-angiogenic
Protocol
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
Methods 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-1.
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)
Doses ~300 mg/kg
Administration Administered orally
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.

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