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869363-13-3 molecular structure
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4-{[13-chloro-10-(2,6-difluorophenyl)-3,5,9-triazatricyclo[9.4.0.0^{2,7}]pentadeca-1(15),2(7),3,5,9,11,13-heptaen-4-yl]amino}benzoic acid

ChemBase ID: 72508
Molecular Formular: C25H15ClF2N4O2
Molecular Mass: 476.8620064
Monoisotopic Mass: 476.08515986
SMILES and InChIs

SMILES:
c1c(cc2c(c1)c1c(CN=C2c2c(cccc2F)F)cnc(n1)Nc1ccc(cc1)C(=O)O)Cl
Canonical SMILES:
Clc1ccc2c(c1)C(=NCc1c2nc(nc1)Nc1ccc(cc1)C(=O)O)c1c(F)cccc1F
InChI:
InChI=1S/C25H15ClF2N4O2/c26-15-6-9-17-18(10-15)23(21-19(27)2-1-3-20(21)28)29-11-14-12-30-25(32-22(14)17)31-16-7-4-13(5-8-16)24(33)34/h1-10,12H,11H2,(H,33,34)(H,30,31,32)
InChIKey:
HHFBDROWDBDFBR-UHFFFAOYSA-N

Cite this record

CBID:72508 http://www.chembase.cn/molecule-72508.html

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NAMES AND DATABASE IDS

NAMES AND DATABASE IDS

Names Database IDs
IUPAC name
4-{[13-chloro-10-(2,6-difluorophenyl)-3,5,9-triazatricyclo[9.4.0.0^{2,7}]pentadeca-1(15),2(7),3,5,9,11,13-heptaen-4-yl]amino}benzoic acid
4-{[13-chloro-10-(2,6-difluorophenyl)-3,5,9-triazatricyclo[9.4.0.02,7]pentadeca-1(11),2(7),3,5,9,12,14-heptaen-4-yl]amino}benzoic acid
IUPAC Traditional name
4-{[13-chloro-10-(2,6-difluorophenyl)-3,5,9-triazatricyclo[9.4.0.0^{2,7}]pentadeca-1(15),2(7),3,5,9,11,13-heptaen-4-yl]amino}benzoic acid
4-{[13-chloro-10-(2,6-difluorophenyl)-3,5,9-triazatricyclo[9.4.0.02,7]pentadeca-1(11),2(7),3,5,9,12,14-heptaen-4-yl]amino}benzoic acid
Synonyms
MLN8054
4-[[9-Chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]benzoic Acid
MLN 8054
CAS Number
869363-13-3
PubChem SID
162037433
PubChem CID
11712649

DATA SOURCES

DATA SOURCES

All Sources Commercial Sources Non-commercial Sources
Data Source Data ID
PubChem 11712649 external link

CALCULATED PROPERTIES

CALCULATED PROPERTIES

JChem
Acid pKa 4.5909085  H Acceptors
H Donor LogD (pH = 5.5) 5.229278 
LogD (pH = 7.4) 3.4550352  Log P 6.06688 
Molar Refractivity 124.4964 cm3 Polarizability 47.014782 Å3
Polar Surface Area 87.47 Å2 Rotatable Bonds
Lipinski's Rule of Five false 

PROPERTIES

PROPERTIES

Physical Property Safety Information Pharmacology Properties Product Information Bioassay(PubChem)
Solubility
Soluble in DMSO expand Show data source
Storage Condition
-20°C expand Show data source
MSDS Link
Download expand Show data source
Target
Aurora Kinase expand Show data source
Salt Data
Free Base expand Show data source
Certificate of Analysis
Download expand Show data source

DETAILS

DETAILS

Selleck Chemicals Selleck Chemicals TRC TRC
Selleck Chemicals - S1100 external link
Research Area
Description Cancer
Biological Activity
Description MLN8054 is a potent and selective inhibitor of Aurora A with IC50 of 4 nM.
Targets Aurora A
IC50 4 nM [1]
In Vitro MLN8054 is an ATP-competitive, reversible inhibitor of recombinant Aurora A kinase with an IC50 of 4 nM, which shows >40-fold more selective inhibitory activity for Aurora A compared with Aurora B. [1] In vitro, MLN8054 exhibits the activity of growth inhibition across various cell lines from diverse tissue origins with IC50 values ranging from 0.11 μM to 1.43 μM. In addition, MLN8054 selectively inhibits Aurora A over Aurora B in cultured cells, and inhibits cell proliferation by promoting G2/M accumulation and spindle defects in multiple cultured human tumor cells lines. [1] A recent study shows that MLN8054 sensitizes androgen-resistant prostate cancer to radiation by inhibiting Aurora A kinase, which is associated with sustained DNA double-strand breaks. [2]
In Vivo In the HCT-116 tumor-bearing mice, MLN8054, administered orally at 3 mg/kg, 10 mg/kg, and 30 mg/kg once a day, leads to dose-dependent tumor growth inhibition (TGI: 76% and 84% for 10 mg/kg and 30 mg/kg). MLN8054 also shows similar antitumor activity in the PC-3 tumor xenograft in nude mice. [1] In the HCT-116 xenograft-bearing animals, MLN8054 induces DNA and tubulin staining of tumor tissue in nuclear and cell body area, consistent with a senescent phenotype by increasing senescence-associated beta-galactosidase activity. [3]
Clinical Trials A Phase I clinical trial has been completed in patients with advanced malignancies.
Features
Protocol
Kinase Assay [1]
Enzyme Assays Recombinant murine Aurora A and Aurora B protein are expressed in Sf9 cells and purified with GST affinity chromatography. The peptide substrate for Aurora A is conjugated with biotin (Biotin-GLRRASLG). Aurora A kinase (5 nM) is assayed in 50 mM Hepes (pH 7.5)/10 mM MgCl2/5 mM DTT/0.05% Tween 20/2 μM peptide substrate/3.3 μCi/ml [γ-33P]ATP at 2 μM by using Image FlashPlates. Aurora B kinase (2 nM) is assayed with 10 μM biotinylated peptide Biotin-TKQTARKSTGGKAPR in 50 mM Tricine (pH 8.0)/2.5 mM MgCl2/5 mM DTT/10% glycerol/2% BSA/40 μCi/ml [γ-33P]ATP at 250 μM. The conditions for all other in vitro kinase assays are available upon request. MLN8054 is run in a 226 kinase screen at a 1 μM compound concentration with an ATP concentration of 10 μM for all assays.
Cell Assay [1]
Cell Lines HCT-116, SW480, DLD-1, MCF-7, MDA-MB-231, Calu-6, H460, SKOV-3 and PC-3 cells
Concentrations 0.04-10 mM
Incubation Time 96 hours
Methods Human tumor cell lines are grown in 96-well cell culture dishes according to the distributor's recommendations. MLN8054, diluted in DMSO, is added to the cells in 2-fold serial dilutions to achieve final concentrations ranging from 10 mM to 0.04 mM. MLN8054 at each dilution is added in triplicate with each replicate on a separate plate. Cells treated with DMSO (n = 6 wells per plate; 0.2% final concentration) serves as the untreated control. The cells are treated with MLN8054 for 96 hours at 37 °C in a humidified cell culture chamber. Cell viability in each cell line is measured by using the Cell Proliferation ELISA, BrdU colorimetric kit according to the manufacturer's recommendations.
Animal Study [1]
Animal Models HCT-116 and PC-3 cells are injected s.c. into the right flank of nude mice.
Formulation MLN8054 is dissolved in 10% hydroxypropyl-β-cyclodextrin with 5% sodium bicarbonate.
Doses ≤30 mg/kg
Administration Administered via p.o.
References
[1] Manfredi MG, et al. Proc Natl Acad Sci U S A, 2007, 104(10), 4106-4111.
[2] Moretti L, et al. Int J Radiat Oncol Biol Phys, 2011, 80(4), 1189-1197.
[3] Huck JJ, et al. Mol Cancer Res, 2010, 8(3), 373-384.
Toronto Research Chemicals - M425125 external link
An Aurora kinase inhibitor, used to treat patients with advanced solid tumors.

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