MLN8054

Catalog No.S1100

MLN8054 is a potent and selective inhibitor of Aurora A with IC50 of 4 nM in Sf9 insect cell. It is more than 40-fold selective for Aurora A than Aurora B. Phase 1.

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MLN8054 Chemical Structure

MLN8054 Chemical Structure
Molecular Weight: 476.86

Validation & Quality Control

3 customer reviews :

Quality Control & MSDS

Related Compound Libraries

MLN8054 is available in the following compound libraries:

Aurora Kinase Inhibitors with Unique Features

Product Information

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  • Research Area
  • Inhibition Profile
  • MLN8054 Mechanism

Product Description

Biological Activity

Description MLN8054 is a potent and selective inhibitor of Aurora A with IC50 of 4 nM in Sf9 insect cell. It is more than 40-fold selective for Aurora A than Aurora B. Phase 1.
Targets Aurora A [1]
(Sf9 cells)
Aurora B [1]
(Sf9 cells)
LCK [1]
(Sf9 cells)
PKA [1]
(Sf9 cells)

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IC50 4 nM 172 nM 3.2 μM 19 μM
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]
Features

Protocol(Only for Reference)

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
Method 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 recommendation

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.
Dosages ≤30 mg/kg
Administration Administered via p.o.

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] 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.

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Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2016-06-25)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT00652158 Terminated Advanced Malignancies Millennium Pharmaceuticals, Inc. April 2006 Phase 1
NCT00249301 Terminated Breast Neoplasm|Colon Neoplasm|Pancreatic Neoplasm|Bladder Neoplasm Millennium Pharmaceuticals, Inc. October 2005 Phase 1

Chemical Information

Download MLN8054 SDF
Molecular Weight (MW) 476.86
Formula

C25H15ClF2N4O2

CAS No. 869363-13-3
Storage 3 years -20℃powder
6 months-80℃in solvent
Synonyms N/A
Solubility (25°C) * In vitro DMSO 95 mg/mL (199.21 mM)
Water <1 mg/mL (<1 mM)
Ethanol <1 mg/mL (<1 mM)
In vivo 15% Captisol 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 Benzoic acid, 4-[[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]-

Customer Product Validation(3)


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Rating
Source Dev Cell 2012 22, 52-63. MLN8054 purchased from Selleck
Method Immunofluorescence
Cell Lines HeLa cells
Concentrations 1 µM
Incubation Time 1 h
Results Treatment of HeLa cells expressing CENP-A-SNAP with inhibitors of either Aurora A or Aurora B did not alterthe G1 phase timing of CENP-A assembly nor did they significantly block Roscovitine-induced CENP-A assembly in G2 phase. These observations suggest that the Aurora kinases are unlikely to be involved in cell cycle control of CENP-A assembly.

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Rating
Source 2013 Professora Dra.maria Gabriela Rodrigues(DBA/FCUL). MLN8054 purchased from Selleck
Method oocyte developmental progress assay
Cell Lines oocytes
Concentrations 0-5 μM
Incubation Time 40 min
Results using  MLN8054 compound, an Aurora‐A inhibitor, decreases oocyte developmental progress and causes spindle anomalies.

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Rating
Source 2011 Dr. Zhang of Tianjin Medical University. MLN8054 purchased from Selleck
Method Western blot
Cell Lines
Concentrations 0.01-10 µM
Incubation Time
Results MLN8054 treatment resulted in a reduction of Aurora A phosphorylation in a does-dependent manner.

Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

Tel: +1-832-582-8158 Ext:3

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
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