MLN0905

Potent PLK1 inhibitor CAS# 1228960-69-7

MLN0905

Catalog No. BCC3961----Order now to get a substantial discount!

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Quality Control of MLN0905

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Chemical structure

MLN0905

3D structure

Chemical Properties of MLN0905

Cas No. 1228960-69-7 SDF Download SDF
PubChem ID 46235922 Appearance Powder
Formula C24H25F3N6S M.Wt 486.56
Type of Compound N/A Storage Desiccate at -20°C
Synonyms PLK1 Inhibitor
Solubility Soluble in DMSO > 10 mM
Chemical Name 2-[[5-[3-(dimethylamino)propyl]-2-methylpyridin-3-yl]amino]-9-(trifluoromethyl)-5,7-dihydropyrimido[5,4-d][1]benzazepine-6-thione
SMILES CC1=C(C=C(C=N1)CCCN(C)C)NC2=NC=C3CC(=S)NC4=C(C3=N2)C=CC(=C4)C(F)(F)F
Standard InChIKey CODBZFJPKJDNDT-UHFFFAOYSA-N
Standard InChI InChI=1S/C24H25F3N6S/c1-14-19(9-15(12-28-14)5-4-8-33(2)3)31-23-29-13-16-10-21(34)30-20-11-17(24(25,26)27)6-7-18(20)22(16)32-23/h6-7,9,11-13H,4-5,8,10H2,1-3H3,(H,30,34)(H,29,31,32)
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of MLN0905

DescriptionMLN0905 is a potent inhibitor of PLK1 with IC50 of 2 nM.
TargetsPLK1    
IC502 nM     

Protocol

Kinase Assay [1]
The human PLK1 enzymatic reaction totaled 30 μL contains 50 mM Tris-HCl (pH 8.0), 10 mM MgCl2, 0.02% BSA, 10% glycerol, 1 mM DTT, 100 mM NaCl, 3.3% DMSO, 50 μM ATP, 2 μM peptide substrate (Biotin-AHX-LDETGHLDSSGLQEVHLA-CONH2), and 0.3 nM recombinant human PLK1[2-369]T210D. The enzymatic reaction mixture, with or without PLK inhibitors, is incubated 90 min at room temperature before termination with 50 μL of STOP buffer containing 1% BSA, 0.05% Tween 20, 100 mM EDTA. Then 50 μL of the stopped enzyme reaction mixture is transferred to a Neutravidin-coated 384-well plate and incubated at room temperature for 60 min. The wells are washed with wash buffer (25 mM Tris, 150 mM sodium chloride, and 0.1% Tween 20) and incubated for 1 h with 50 μL of antibody reaction mixture containing 1% BSA, 0.05% Tween 20, antiphospho-cdc25c rabbit monoclonal antibody (325 pM), and europium labeled antirabbit IgG (2 nM). The wells are washed, and then the bound europium is liberated using 50 μL of Enhancement Solution. Quantification of europium is done using a Pherastar[1].

Cell Assay [1]
Eight μL of serially diluted test compounds are added to75 μL of HT29 (2.66×104 cells/well) cells in McCoy’s 5A media supplemented with 10% Fetal Calf Serum in Biocoat Poly-D lysine 384 well Black/Clear plates. Cells are incubated for 72 h at 37°C. Supernatant is aspirated from the wells, leaving 25 μL in each well. ATP-lite 1 step reagent (25 μL) is added to each well, and luminescence for each plate is read on the LeadSeeker. Percent inhibition is calculated using the values from a DMSO control set to 100%[1].

Animal Administration [1]
HT29 cells are obtained from ATCC and are cultured in McCoy’s 5A medium supplemented with 10% FBS. HT29 cells (2×106) are resuspended in Hanks buffer and injected subcutaneously into the flanks of female Nude mice. Mice (10 animals/group) are treated orally with 12c (MLN0905) for 21 days at doses based on tolerability results: QD (6.25 and 12.5 mg/kg), QD×1/week (50 mg/kg), and QD×3/week (25 mg/kg). Tumor growth is monitored using vernier calipers, and the mean tumor volume is calculated using the formula V = W2 × L/2. When the mean tumor volume reaches approximately 200 mm3, the animals are randomized into treatment groups (n = 10 animals/group). Tumor growth and body weights are measured twice per week[1].

References:
[1]. Duffey MO, et al. Discovery of a potent and orally bioavailable benzolactam-derived inhibitor of Polo-like kinase 1 (MLN0905). J Med Chem. 2012 Jan 12;55(1):197-208. [2]. Shi JQ, et al. MLN0905, a small-molecule plk1 inhibitor, induces antitumor responses in human models of diffuse large B-cell lymphoma. Mol Cancer Ther. 2012 Sep;11(9):2045-53.

MLN0905 Dilution Calculator

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MLN0905 Molarity Calculator

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Preparing Stock Solutions of MLN0905

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.0552 mL 10.2762 mL 20.5524 mL 41.1049 mL 51.3811 mL
5 mM 0.411 mL 2.0552 mL 4.1105 mL 8.221 mL 10.2762 mL
10 mM 0.2055 mL 1.0276 mL 2.0552 mL 4.1105 mL 5.1381 mL
50 mM 0.0411 mL 0.2055 mL 0.411 mL 0.8221 mL 1.0276 mL
100 mM 0.0206 mL 0.1028 mL 0.2055 mL 0.411 mL 0.5138 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on MLN0905

MLN0905 is a potent inhibitor of PLK1 with IC50 value ranges from 3 to 24 nM [1].

Polo-like kinase 1 (PLK1) is a family of conserved serine/threonine kinases and plays an important role in regulating cell cycle. It has been revealed that PLK1 drives cell cycle progression by triggerting G2/M transition and is considered as a pro-oncogene which overexpressed in tumor cells [2].

MLN0905 is a selective PLK1 inhibitor and has similar effect as RNAi hnockdown. When tested with HT-29 cells, MLN0905 treatment significantly increased pHisH3 expression which indicated that cells were arrested in G2/M phase by inhibiting PLK1 expression [1].

In mouse model with human diffuse large B-cell lymphoma (DLBCL) cell line OCILY-19 subcutaneous xenograft, co-administration of MLN0905 and rituximab markedly reduced tumor volume and increased survival time through inhibiting PLK1 which resulted in mitotic arrest [1]. And the same result was achieved when using nude mice model with human colon tumor HT29 xenograft, MLN0905 treatment significantly inhibited tumor growth or progression [3].

References:
[1].  Shi, J.Q., et al., MLN0905, a small-molecule plk1 inhibitor, induces antitumor responses in human models of diffuse large B-cell lymphoma. Mol Cancer Ther, 2012. 11(9): p. 2045-53.
[2].  Espeut, J., et al., Natural Loss of Mps1 Kinase in Nematodes Uncovers a Role for Polo-like Kinase 1 in Spindle Checkpoint Initiation. Cell Rep, 2015.
[3].   Duffey, M.O., et al., Discovery of a potent and orally bioavailable benzolactam-derived inhibitor of Polo-like kinase 1 (MLN0905). J Med Chem, 2012. 55(1): p. 197-208.

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References on MLN0905

Discovery of a potent and orally bioavailable benzolactam-derived inhibitor of Polo-like kinase 1 (MLN0905).[Pubmed:22070629]

J Med Chem. 2012 Jan 12;55(1):197-208.

This article describes the discovery of a series of potent inhibitors of Polo-like kinase 1 (PLK1). Optimization of this benzolactam-derived chemical series produced an orally bioavailable inhibitor of PLK1 (12c, MLN0905). In vivo pharmacokinetic-pharmacodynamic experiments demonstrated prolonged mitotic arrest after oral administration of 12c to tumor bearing nude mice. A subsequent efficacy study in nude mice achieved tumor growth inhibition or regression in a human colon tumor (HT29) xenograft model.

MLN0905, a small-molecule plk1 inhibitor, induces antitumor responses in human models of diffuse large B-cell lymphoma.[Pubmed:22609854]

Mol Cancer Ther. 2012 Sep;11(9):2045-53.

Diffuse large B-cell lymphoma (DLBCL) is the most common of the non-Hodgkin lymphomas, accounting for up to 30% of all newly diagnosed lymphoma cases. Current treatment options for this disease are effective, but not always curative; therefore, experimental therapies continue to be investigated. We have discovered an experimental, potent, and selective small-molecule inhibitor of PLK1, MLN0905, which inhibits cell proliferation in a broad range of human tumor cells including DLBCL cell lines. In our report, we explored the pharmacokinetic, pharmacodynamic, and antitumor properties of MLN0905 in DLBCL xenograft models grown in mice. These studies indicate that MLN0905 modulates the pharmacodynamic biomarker phosphorylated histone H3 (pHisH3) in tumor tissue. The antitumor activity of MLN0905 was evaluated in three human subcutaneous DLBCL xenograft models, OCI LY-10, OCI LY-19, and PHTX-22L (primary lymphoma). In each model, MLN0905 yielded significant antitumor activity on both a continuous (daily) and intermittent dosing schedule, underscoring dosing flexibility. The antitumor activity of MLN0905 was also evaluated in a disseminated xenograft (OCI LY-19) model to better mimic human DLBCL disease. In the disseminated model, MLN0905 induced a highly significant survival advantage. Finally, MLN0905 was combined with a standard-of-care agent, rituximab, in the disseminated OCI LY-19 xenograft model. Combining rituximab and MLN0905 provided both a synergistic antitumor effect and a synergistic survival advantage. Our findings indicate that PLK1 inhibition leads to pharmacodynamic pHisH3 modulation and significant antitumor activity in multiple DLBCL models. These data strongly suggest evaluating PLK1 inhibitors as DLBCL anticancer agents in the clinic.

Description

MLN0905 is a potent inhibitor of PLK1 with IC50 of 2 nM.

Keywords:

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