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MLN0905

Names

[ CAS No. ]:
1228960-69-7

[ Name ]:
MLN0905

[Synonym ]:
2-({5-[3-(dimethylamino)propyl]-2-methylpyridin-3-yl}amino)-9-(trifluoromethyl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepine-6-thione
CS-1081
9-trifluoromethyl-2-({5-[3-(dimethylamino)propyl]-2-methylpyridin-3-yl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepine-6-thione
2-(5-(3-(DIMETHYLAMINO)PROPYL)-2-METHYLPYRIDIN-3-YLAMINO)-9-(TRIFLUOROMETHYL)-5H-BENZO[B]PYRIMIDO[4,5-D]AZEPINE-6(7H)-THIONE
6H-Pyrimido[5,4-d][1]benzazepine-6-thione, 2-[[5-[3-(dimethylamino)propyl]-2-methyl-3-pyridinyl]amino]-5,7-dihydro-9-(trifluoromethyl)-
MLN0905
QC-9272
2-({5-[3-(Dimethylamino)propyl]-2-methyl-3-pyridinyl}amino)-9-(trifluoromethyl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepine-6-thione

Biological Activity

[Description]:

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

[Related Catalog]:

Signaling Pathways >> Cell Cycle/DNA Damage >> Polo-like Kinase (PLK)
Research Areas >> Cancer

[Target]

PLK1:2 nM (IC50)


[In Vitro]

MLN0905 (compound 12c) exhibits potent activities with an EC50 of 33 ± 21 nM for Cdc25C. MLN0905 shows inhibitory effects on HT29, HCT116, H460, and A375 cell lines, with LD50s of 22, 56, 89, and 34 nM[1]. MLN0905 (125 nM) yields strong mitotic arrest and monopolar spindle formation in HT-29 cells, and these effects are associated with PLK1 inhibition. MLN0905 suppresses lymphoma cell lines with IC50 values ranging from 3 to 24 nM[2].

[In Vivo]

MLN0905 (50 mg/kg, p.o.) shows a higher sustained PD response as it impressively generates a robust PD response up to 72 h in nude mice bearing HT29 xenograft tumors. MLN0905 (6.25, 12.5, 25, 50 mg/kg, p.o.) exhibits significant antitumor activities in mice bearing HT29 xenograft tumors[1]. MLN0905 has marked antitumor effects in a subcutaneous OCI LY-19-Luc lymphoma xenograft model, and the treatment are as follows: 3.12 mg/kg daily, 6.25 mg/kg daily, 10 mg/kg QD×3/wk, and 14.5 mg/kg QD×3/wk. MLN0905 (1.6, 3.12, and 6.25 mg/kg, p.o.) also induces a significant antitumor response in mice bearing disseminated (human) OCI LY-19-Luc lymphoma disease. MLN0905 (6, 8, 10, 12.5, and 14.5 mg/kg, p.o.) causes a significant antitumor response in a primary human lymphoma model (PHTX-22L). Furthermore, MLN0905 synergizes with rituximab in a disseminated OCI LY-19-Luc lymphoma model[2].

[Kinase Assay]

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]

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 admin]

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.


[Related Small Molecules]

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Chemical & Physical Properties

[ Density]:
1.4±0.1 g/cm3

[ Boiling Point ]:
624.4±65.0 °C at 760 mmHg

[ Molecular Formula ]:
C24H25F3N6S

[ Molecular Weight ]:
486.556

[ Flash Point ]:
331.4±34.3 °C

[ Exact Mass ]:
486.181335

[ PSA ]:
105.10000

[ LogP ]:
4.60

[ Vapour Pressure ]:
0.0±1.8 mmHg at 25°C

[ Index of Refraction ]:
1.640

[ Storage condition ]:
-20℃

Synthetic Route

Click to get detail synthetic route

Precursor & DownStream

Precursor

DownStream