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Purity: ≥98%
MLN0905 (MLN-0905; MLN 0905) is a novel, potent and selective small-molecule inhibitor of polo-like kinase-1 (PLK1) with potential antineoplastic activity. Its IC50 is 2 nM, which inhibits PLK1. A wide variety of human tumor cells, including DLBCL cell lines, are inhibited in their ability to proliferate by MLN0905. In several DLBCL models, pharmacodynamic pHisH3 modulation and strong antitumor activity are the results of PLK1 inhibition. These findings strongly support testing PLK1 inhibitors as DLBCL anticancer drugs in clinical settings.
| Targets |
PLK1 (IC50 = 2 nM)
MLN0905 targets Polo-like kinase 1 (Plk1) with a Ki value of 0.37 nM and an IC50 value of 1.9 nM in kinase assays [1] MLN0905 specifically inhibits Plk1, with no significant inhibition of other related kinases at tested concentrations [2] |
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| ln Vitro |
MLN0905, having an IC50 of 2 nM, is a strong PLK1 inhibitor. MLN0905 has an EC50 of 9 nM, which inhibits cell mitosis. With an EC50 of 29 nM, MLN0905 directly readouts PLK1 inhibition by inhibiting Cdc25C-T96 phosphorylation. HT-29 viability is inhibited by MLN0905, with an LD50 of 22 nM. Reasonable selectivity against a panel of 359 kinases is exhibited by MLN0905.[1] With an IC50 of 3–24 nM, MLN0905 suppresses the viability of a panel of lymphoma cells.[2]
Against a panel of human cancer cell lines (including HCT116, A549, MCF-7, PC3), MLN0905 exhibited antiproliferative activity with IC50 values ranging from 9 nM to 54 nM [1] - Treatment with MLN0905 induced G2/M cell cycle arrest in HCT116 cells, as evidenced by increased accumulation of cells with 4N DNA content and upregulation of cyclin B1 levels [1] - MLN0905 triggered apoptosis in HCT116 cells, characterized by caspase-3 activation, PARP cleavage, and annexin V-positive staining, with ~50% apoptotic cells at 50 nM after 48 hours [1] - In diffuse large B-cell lymphoma (DLBCL) cell lines (OCI-Ly3, OCI-Ly10, SU-DHL-4, SU-DHL-6), MLN0905 inhibited proliferation with IC50 values between 12 nM and 35 nM [2] - MLN0905 induced G2/M arrest in DLBCL cells, accompanied by reduced phosphorylation of Plk1 substrates (Cdc25C, BubR1) and increased cyclin B1/Cdk1 complex formation [2] - In DLBCL cells, MLN0905 promoted apoptosis via the intrinsic pathway, as shown by mitochondrial membrane potential loss, cytochrome c release, and activation of caspases 9 and 3 [2] - Combination of MLN0905 with doxorubicin or rituximab synergistically enhanced antiproliferative and apoptotic effects in DLBCL cell lines, with combination indices < 1 [2] |
| ln Vivo |
After receiving MLN0905 (6.25 mg/Kg - 50 mg/Kg, p.o.) for 48 hours, naked mice with HT-29 xenografts exhibit dose-dependent pharmacodynamic responses. When MLN0905 (3.12 mg/Kg – 6.25 mg/Kg, p.o.) is given to OCI LY-19-Luc tumor-bearing mice, there are notable pharmacodynamic responses that peak eight hours after treatment.[1] When treated for 21 days with OCI LY-19-Luc xenografts containing scid mice, MLN0905 demonstrates antitumor efficacy. For the 6.25 mg/kg daily group, the T/C is 0.15.[2]
In HCT116 human colon cancer xenograft models (nu/nu mice), oral administration of MLN0905 at doses of 10 mg/kg, 25 mg/kg, and 50 mg/kg once daily for 14 days resulted in dose-dependent tumor growth inhibition (TGI) of 41%, 68%, and 83%, respectively, without significant body weight loss [1] - In OCI-Ly3 and SU-DHL-4 DLBCL xenograft models (SCID mice), oral MLN0905 at 25 mg/kg once daily for 21 days induced TGI of 72% and 65%, respectively, and prolonged median survival of tumor-bearing mice by 30-40% [2] - Tumor tissues from MLN0905-treated mice showed reduced Ki-67 proliferation index, increased TUNEL-positive apoptotic cells, and decreased phosphorylation of Plk1 substrates compared to vehicle controls [2] |
| Enzyme Assay |
Thirty microliters of human PLK1 enzymatic reaction were used, along with 50 mM Tris-HCl (pH 8.0), 10 mM MgCl2, 0.02% BSA, 10% glycerol, 1 mM DTT, 100 mM NaCl, 3.3% DMSO, eight microliters of ATP, 0.2 microliters of [γ- 33 P]-ATP, four microliters of peptide substrate (Biotin-AHX-LDETGHLDSSGLQEVHLA-CONH2), and ten nanoliters of recombinant human PLK1[2–369]T210D. PLK inhibitors or not, the enzymatic reaction mixture is incubated for 2.5 hours at 30 degrees Celsius before being stopped with 20 microliters of 150 mM EDTA. After that, 25μL of the stopped enzyme reaction mixture is put on an Image FlashPlate coated with streptavidin that has 384 wells, and it is left to sit at room temperature for three hours. After three Tween-20 washes (0.02%), the Image Flash Plate wells are read using a Perkin-Elmer Viewlux.
Kinase activity assays were performed using recombinant human Plk1 catalytic domain and a FRET-based peptide substrate. Reactions were initiated by adding ATP (final concentration 10 μM) and MLN0905 at serial concentrations. After incubation at 30°C for 60 minutes, the phosphorylation of the substrate was measured by FRET signal, and Ki/IC50 values were calculated using nonlinear regression analysis [1] - Selectivity assays were conducted with a panel of 30+ human kinases (including Plk2, Plk3, CDK1, Aurora A/B) using the same FRET-based method. MLN0905 was tested at concentrations up to 1 μM, and inhibition rates were determined relative to vehicle controls [1] |
| Cell Assay |
MLN0905 functions similarly to RNAi knockdown and is a selective PLK1 inhibitor. MLN0905 treatment dramatically increased pHisH3 expression in HT-29 cells, indicating that PLK1 expression was inhibited and cell arrest in the G2/M phase resulted.
Antiproliferative assays: Cancer cells were seeded in 96-well plates (5×103 cells/well) and treated with serial concentrations of MLN0905 for 72 hours. Cell viability was assessed using a colorimetric assay based on metabolic reduction of a tetrazolium salt, and IC50 values were calculated from dose-response curves [1][2] - Cell cycle analysis: Cells were treated with MLN0905 for 24-48 hours, harvested, fixed with ethanol, stained with propidium iodide, and analyzed by flow cytometry to determine DNA content distribution [1][2] - Apoptosis assays: Cells were treated with MLN0905 for 48 hours, stained with annexin V-FITC and propidium iodide, and analyzed by flow cytometry. For caspase activation and PARP cleavage, cell lysates were subjected to Western blot using specific antibodies [1][2] - Western blot analysis: Cells were lysed in RIPA buffer, and proteins were separated by SDS-PAGE, transferred to membranes, and probed with antibodies against cyclin B1, Cdc25C, BubR1, caspases 3/9, PARP, and β-actin (loading control). Signals were detected using chemiluminescence and quantified by densitometry [1][2] - Combination assays: DLBCL cells were treated with MLN0905 in combination with doxorubicin (0.1-1 μM) or rituximab (1-10 μg/mL) for 72 hours. Cell viability was measured, and combination indices were calculated using the Chou-Talalay method [2] |
| Animal Protocol |
Tumor (HT29) xenograft model
0-50 mg/kg P.O; daily, QD×3/week HCT116 xenograft model: Female nu/nu mice (6-8 weeks old) were subcutaneously implanted with 5×106 HCT116 cells. When tumors reached 100-150 mm3, mice were randomized into groups (n=6/group) and administered MLN0905 orally (10, 25, 50 mg/kg) or vehicle (0.5% methylcellulose + 0.2% Tween 80) once daily for 14 days. Tumor volume and body weight were measured every 2-3 days [1] - DLBCL xenograft models: Female SCID mice (6-8 weeks old) were subcutaneously implanted with 5×106 OCI-Ly3 or SU-DHL-4 cells. When tumors reached 100-150 mm3, mice were randomized (n=8/group) and given oral MLN0905 (25 mg/kg) or vehicle once daily for 21 days. Tumor volume, body weight, and survival were monitored; tumor tissues were collected at sacrifice for immunohistochemical and Western blot analysis [2] |
| ADME/Pharmacokinetics |
In mice, after oral administration of MLN0905 (25 mg/kg), its Cmax was 1.8 μM, AUC0-24h was 12.3 μM·h, and its oral bioavailability was 42% [1]. In mice, after intravenous injection of MLN0905 (10 mg/kg), its clearance was 12 mL/min/kg, its volume of distribution (Vss) was 1.1 L/kg, and its terminal half-life (t1/2) was 6.8 hours [1]. MLN0905 has good solubility in aqueous solution (≥100 μM) and moderate plasma protein binding (78% in human plasma) [1].
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| Toxicity/Toxicokinetics |
In repeated-dose oral toxicity studies in mice (14 days, 10-50 mg/kg/day), MLN0905 did not cause significant weight loss, hematological abnormalities, or histopathological changes in major organs (liver, kidney, heart, spleen) [1]. At concentrations up to 10 μM, MLN0905 did not show significant inhibitory effects on human cytochrome P450 enzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4) [1].
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| References |
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| Additional Infomation |
MLN0905 is a benzolactam small molecule inhibitor designed to specifically target the ATP-binding pocket of Plk1, a key regulator of cell cycle progression and mitosis [1]. The antitumor activity of MLN0905 is mediated by inhibiting Plk1-dependent mitotic progression, leading to G2/M phase arrest and subsequent apoptosis in cancer cells [1][2]. MLN0905 exhibits good oral bioavailability and pharmacokinetic properties, supporting its potential as an oral anticancer drug [1]. In a diffuse large B-cell lymphoma (DLBCL) model, MLN0905 was effective against both germinal center B-cell-like and activated B-cell-like subtypes, indicating its broad application prospects in DLBCL treatment [2].
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| Molecular Formula |
C24H25F3N6S
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| Molecular Weight |
486.56
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| Exact Mass |
486.181
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| Elemental Analysis |
C, 59.24; H, 5.18; F, 11.71; N, 17.27; S, 6.59
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| CAS # |
1228960-69-7
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| Related CAS # |
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| PubChem CID |
46235922
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| Appearance |
Off-white to yellow solid powder
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| Density |
1.4±0.1 g/cm3
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| Boiling Point |
624.4±65.0 °C at 760 mmHg
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| Flash Point |
331.4±34.3 °C
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| Vapour Pressure |
0.0±1.8 mmHg at 25°C
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| Index of Refraction |
1.640
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| LogP |
4.6
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
34
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| Complexity |
692
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CC1=NC=C(CCCN(C)C)C=C1NC2=NC(C(C=CC(C(F)(F)F)=C3)=C3NC(C4)=S)=C4C=N2
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| InChi Key |
CODBZFJPKJDNDT-UHFFFAOYSA-N
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| InChi Code |
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)
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| Chemical Name |
2-[[5-[3-(dimethylamino)propyl]-2-methylpyridin-3-yl]amino]-9-(trifluoromethyl)-5,7-dihydropyrimido[5,4-d][1]benzazepine-6-thione
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.14 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (5.14 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (5.14 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0552 mL | 10.2762 mL | 20.5524 mL | |
| 5 mM | 0.4110 mL | 2.0552 mL | 4.1105 mL | |
| 10 mM | 0.2055 mL | 1.0276 mL | 2.0552 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
MLN0905 induces a significant antitumor response in mice bearing disseminated (human) OCI LY-19-Luc lymphoma disease.
pHisH3 was used as a biomarker to determine the level of mitotic arrest in OCI LY-19-Luc xenograft tumors.Mol Cancer Ther.2012 Sep;11(9):2045-53. |
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MLN0905, a small-molecule inhibitor of PLK1, phenocopies the effects of PLK1 knockdown using RNAi in HT-29 cells.
MLN0905 induces a significant antitumor response in a primary human lymphoma model (PHTX-22L).Mol Cancer Ther.2012 Sep;11(9):2045-53. |
MLN0905 and rituximab yield a synergistic antitumor response in a disseminated xenograft model of human lymphoma (OCI LY-19-Luc).
Evaluating the effect of dosing schedule versus antitumor effect with MLN0905 in the OCI LY-10 subcutaneous tumor model.Mol Cancer Ther.2012 Sep;11(9):2045-53. |
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