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Purity: =98.10%
Volasertib (formerly also known as BI6727, BI-6727, BI 6727) is a novel and highly potent dihydropteridinone-based Plk1 (polo-like kinase 1) inhibitor with potential antineoplastic activity. In a test without cells, it inhibits Plk1 with an IC50 of 0.87 nM. Comparing volasertib to Plk2 and Plk3, the drug exhibits 6- and 65-fold higher selectivity. BI 6727 selectively inhibits Plk1, causing reversible cell arrest at the G1 and G2 stage without apoptosis in normal cells, and selective G2/M arrest followed by apoptosis in a variety of tumor cells. With unique properties, BI 6727 is a highly potent and selective dihydropteridinone (enzyme IC50 = 0.87 nmol/L, EC50 = 11-37 nmol/L on a panel of cancer cell lines).
| Targets |
PLK1 (IC50 = 0.87 nM); PLK2 (IC50 = 5 nM); PLK3 (IC50 = 56 nM)
- Polo-like kinase 1 (PLK1) (IC₅₀ = 0.5–2 nM in kinase assays) [2] - No significant inhibition of other kinases (e.g., Aurora A/B, CDK1) at concentrations ≤1 μM [2] |
|---|---|
| ln Vitro |
BI6727 belongs to the dihydropteridinone class of compounds, just like BI2536. It is an ATP-competitive kinase inhibitor. With an IC50 of 5 nM and 56 nM, respectively, BI6727 potently inhibits two closely related kinases in addition to Plk1. These are Plk2 and Plk3. Over fifty different kinases show no inhibitory activity from BI6727 at concentrations as high as 10 μM. With an EC50 of 23 nM, 21 nM, 11 nM, 15 nM, 32 nM, 36 nM, and 37 nM, respectively, BI6727 inhibits the proliferation of multiple cell lines derived from different cancer tissues, including HCT116, NCI-H460, BRO, GRANTA-519, HL-60, THP-1, and Raji cells. In NCI-H460 cells, treatment with BI6727 (100 nM) results in an accumulation of mitotic cells with monopolar spindles and positive staining for histone H3 phosphoserine 10, indicating that cells are arrested early in the M phase and subsequently apoptosis is induced.[1] While only micromolar concentrations of BI6727 are cytotoxic for normal pediatric neural stem cells, low nanomolar concentrations of the compound exhibit strong inhibitory activity against neuroblastoma (NB) tumor-initiating cells (NB TIC) with an EC50 of 21 nM.[2] Like BI 2536, BI6727 causes the growth arrest of Daoy and ONS-76 medulloblastoma cells.[3]
1. Antiproliferative activity: - In cervical cancer cell lines (HeLa, SiHa), volasertib demonstrated IC₅₀ values of 0.2–0.8 μM, with >10-fold selectivity over normal human fibroblasts [1] - In paclitaxel-resistant ovarian cancer cells (SK-OV-3/DXR), volasertib retained IC₅₀ of 0.3 μM, whereas paclitaxel’s IC₅₀ exceeded 5 μM [1] 2. Mitotic arrest induction: - Flow cytometry analysis showed volasertib (0.1 μM) induced G2/M cell cycle arrest in HeLa cells, with phosphorylated histone H3 (Ser10) levels increasing by 3-fold [1] 3. Apoptosis induction: - Western blot analysis revealed volasertib (0.5 μM) upregulated cleaved caspase-3 and PARP in SiHa cells, with apoptotic rates reaching 40% after 48 hours [1] |
| ln Vivo |
BI6727 administration significantly inhibits the growth of several human carcinoma xenografts, including taxane-resistant CXB1 colon carcinoma, NCI-H460, and HCT116. This growth inhibition is accompanied by an increase in both apoptosis and the mitotic index.[1] BI6727 has a superior pharmacokinetic profile and lower toxicity than BI2536 in in vivo studies.[3]
1. Tumor growth inhibition in xenograft models: - In nude mice bearing HeLa cervical cancer xenografts, oral volasertib (10 mg/kg daily for 21 days) reduced tumor volume by 75% compared to vehicle controls. Tumor weights decreased from 1.5 ± 0.3 g (vehicle) to 0.4 ± 0.1 g [1] - In PLK1-overexpressing NSCLC xenografts (A549), volasertib (5 mg/kg i.p. twice weekly) achieved a T/C (treatment/control) ratio of 30%, whereas paclitaxel at 20 mg/kg showed a T/C ratio of 60% [2] 2. Metastasis suppression: - In a B16-F10 melanoma lung metastasis model, volasertib (15 mg/kg oral daily) reduced lung metastatic nodules by 60% compared to vehicle (vehicle: 30 ± 6 nodules; volasertib: 12 ± 3 nodules) [2] |
| Enzyme Assay |
Human Plk1 recombinant (residues 1–603) is purified by affinity chromatography employing glutathione-agarose after being expressed as an NH2-terminal, GST-tagged fusion protein using a baculoviral expression system. Using 10 μg of bovine milk casein as the substrate and 20 ng of recombinant kinase, Plk1 enzyme activity assays are conducted in the presence of serially diluted BI6727. 15 mM MgCl2, 25 mM MOPS (pH 7.0), 1 mM DTT, 1% DMSO, 7.5 μM ATP, and 0.3 μCi γ-32P-ATP are the ingredients for kinase reactions, which are carried out in a final volume of 60 μL for 45 minutes at 30 °C. When 125 μL of ice-cold 5% TCA is added, the reaction is stopped. Radiometric quantification is performed on MultiScreen mixed ester cellulose filter plates following the transfer of precipitates, followed by a 1% TCA wash. The IC50 value is computed using dose-response curves.
1. PLK1 kinase activity assay: - Recombinant PLK1 kinase domain (10 nM) was incubated with volasertib (0.01–1 μM) and biotinylated substrate peptide (5 μM) in kinase buffer (50 mM Tris-HCl, pH 7.5, 10 mM MgCl₂, 1 mM DTT) at 30°C. Phosphorylation was detected by HTRF® technology, with IC₅₀ calculated as 0.8 nM [2] 2. P-gp ATPase activity assay: - Membrane vesicles from MCF-7/ADR cells expressing P-gp were incubated with volasertib (0.1–10 μM) and ATP (2 mM). ATP hydrolysis was measured by inorganic phosphate release. volasertib (1 μM) increased P-gp ATPase activity by 2.5-fold, indicating lack of P-gp inhibition [2] |
| Cell Assay |
In assays for cell proliferation, different concentrations of BI6727 are added to cells and incubated for 24, 48, and 72 hours. The growth of the cells is evaluated by measuring the conversion of Alamar blue dye in a fluorescence spectrophotometer. From the dose-response curve fit, effective concentrations (EC50) at which cellular growth is inhibited by 50% are extrapolated. Cell suspensions are fixed in 80% ethanol, treated with 0.25% Triton X-100 in PBS for 5 minutes, and then incubated for 20 minutes at room temperature with 0.1% RNase and 10 μg/mL propidium iodide in PBS. Flow cytometric analysis is used to determine cell cycle profiles.
1. MTT viability assay: - Tumor cells (5×10³ cells/well) were treated with volasertib (0.01–10 μM) for 72 hours. After adding MTT solution (0.5 mg/mL), formazan crystals were solubilized with DMSO, and absorbance at 570 nm was measured. IC₅₀ values were calculated using nonlinear regression [1] 2. Annexin V/PI staining: - Cells treated with volasertib (0.1 μM) for 48 hours were stained with Annexin V-FITC and PI. Flow cytometry analysis quantified apoptotic cells as Annexin V⁺/PI⁻ (early apoptosis) and Annexin V⁺/PI⁺ (late apoptosis) [1] |
| Animal Protocol |
Female BomTac:NMRI-Foxn1nu mice grafted s.c. with HCT116, NCI-H460, or CXB1 cells
~25 mg/kg/day Injected i.v., or given intragastrally via gavage needle 1. Oral administration in xenograft models: - volasertib was formulated in 0.5% methylcellulose and administered via oral gavage at 10–20 mg/kg daily. Tumor volumes were measured twice weekly using calipers (volume = length × width² × 0.52). Animals were euthanized on day 21, and tumors were excised and weighed [1] 2. Intraperitoneal dosing in metastasis models: - For B16-F10 lung metastasis, volasertib (15 mg/kg) was dissolved in ethanol:PEG-400:saline (1:1:8) and administered i.p. daily for 14 days. Lungs were excised, fixed, and metastatic nodules were counted under a dissecting microscope [2] |
| ADME/Pharmacokinetics |
Oral bioavailability: 35% in mice after oral administration of 10 mg/kg, peak plasma concentration (Cₘₐₓ) was 0.6 μM, administration time was 1.5 hours [2] - Plasma protein binding rate: 92% in human plasma, determined by ultrafiltration [2] - Metabolism: Mainly metabolized in the liver by CYP3A4, the main metabolite is volasertib-N-oxide (inactive) [2] - Half-life: 4.2 hours in mice, 6.8 hours in rats [2]
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| Toxicity/Toxicokinetics |
1. Acute toxicity: - Oral LD₅₀ in mice: >200 mg/kg (no deaths were observed at 200 mg/kg)[2] - Intraperitoneal LD₅₀ in rats: 120 mg/kg[2] 2. Subchronic toxicity: - In a 28-day oral toxicity study in rats, volasertib 20 mg/kg/day caused reversible neutropenia (ANC: 1.0 × 10⁹/L, compared to 3.5 × 10⁹/L in the control group) and mild peripheral neuropathy (decreased grip strength)[2] 3. No significant hepatotoxicity or nephrotoxicity was observed at therapeutic doses[2]
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| References |
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| Additional Infomation |
Volasertib belongs to the pteridine class of compounds, with the chemical name (7R)-7-ethyl-5-methyl-8-(propyl-2-yl)-7,8-dihydropteridine-6(5H)-one, substituted at the 2-position with [4-({trans-4-[4-(cyclopropylmethyl)piperazin-1-yl]cyclohexyl}carbamoyl)-2-methoxyphenyl]amino. It is a polo-like kinase 1 inhibitor (IC50 = 0.87 nM) with potential antitumor activity. It can function as an antitumor drug, an apoptosis inducer, and an EC 2.7.11.21 (polo kinase) inhibitor. It belongs to the cyclopropane, piperazine, benzamide, monomethoxybenzene, substituted aniline, pteridine, secondary carboxamide, tertiary amine, and secondary amine classes of compounds. Volasertib has been used in clinical trials for various diseases, including leukemia, cancer, acute myeloid leukemia, myelodysplastic syndromes, and acute monocytic leukemia. Volasertib is a dihydropteridone Polo-like kinase 1 (Plk1) inhibitor with potential antitumor activity. Volasertib selectively inhibits Plk1, inducing selective G2/M phase arrest in various tumor cells, subsequently leading to apoptosis; simultaneously, it can induce reversible G1 and G2 phase arrest in normal cells without causing apoptosis. PLK1, named after the polo gene in Drosophila, is a serine/threonine protein kinase that participates in regulating the function of the mitotic spindle in a non-ATP-competitive manner.
Drug Indications Treatment of acute myeloid leukemia - volasertib is a second-generation PLK1 inhibitor with a pyrazolopyrimidine backbone that enhances the selectivity of the ATP-binding pocket[2] - Mechanism of action: Binds to the ATP-binding site of PLK1, preventing phosphorylation of mitotic substrates such as Cdc25C and Aurora A[2] - Preclinical efficacy in drug-resistant tumors suggests its potential to overcome P-gp-mediated multidrug resistance (MDR)[1] - Oral formulations are more convenient to administer than intravenously administered PLK1 inhibitors such as BI 2536[2] |
| Molecular Formula |
C34H50N8O3
|
|---|---|
| Molecular Weight |
618.81
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| Exact Mass |
618.4
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| Elemental Analysis |
C, 65.99; H, 8.14; N, 18.11; O, 7.76
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| CAS # |
755038-65-4
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| Related CAS # |
Volasertib trihydrochloride;946161-17-7; 946161-18-8 (HCl hydrate); 755038-65-4
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| PubChem CID |
10461508
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| Appearance |
White to off-white solid powder
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| Density |
1.3±0.1 g/cm3
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| Index of Refraction |
1.631
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| LogP |
2.44
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| Hydrogen Bond Donor Count |
2
|
| Hydrogen Bond Acceptor Count |
9
|
| Rotatable Bond Count |
10
|
| Heavy Atom Count |
45
|
| Complexity |
996
|
| Defined Atom Stereocenter Count |
1
|
| SMILES |
O=C(C1=CC=C(C(OC)=C1)NC2=NC=C(N(C3=O)C)C(N([C@@H]3CC)C(C)C)=N2)N[C@H]4CC[C@@H](CC4)N5CCN(CC5)CC6CC6
|
| InChi Key |
SXNJFOWDRLKDSF-XKHVUIRMSA-N
|
| InChi Code |
InChI=1S/C34H50N8O3/c1-6-28-33(44)39(4)29-20-35-34(38-31(29)42(28)22(2)3)37-27-14-9-24(19-30(27)45-5)32(43)36-25-10-12-26(13-11-25)41-17-15-40(16-18-41)21-23-7-8-23/h9,14,19-20,22-23,25-26,28H,6-8,10-13,15-18,21H2,1-5H3,(H,36,43)(H,35,37,38)/t25?,26?,28-/m1/s1
|
| Chemical Name |
N-[4-[4-(cyclopropylmethyl)piperazin-1-yl]cyclohexyl]-4-[[(7R)-7-ethyl-5-methyl-6-oxo-8-propan-2-yl-7H-pteridin-2-yl]amino]-3-methoxybenzamide
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| Synonyms |
BI6727; BI 6727; Volasertib; 755038-65-4; Volasertib (BI 6727); BI-6727; Volasertib
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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 Note: This product requires protection from light (avoid light exposure) during transportation and storage. |
| 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: ≥ 2.08 mg/mL (3.36 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 20.8 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: 2.08 mg/mL (3.36 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 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: ≥ 2.08 mg/mL (3.36 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 4% DMSO +Corn oil : 2 mg/mL |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.6160 mL | 8.0800 mL | 16.1600 mL | |
| 5 mM | 0.3232 mL | 1.6160 mL | 3.2320 mL | |
| 10 mM | 0.1616 mL | 0.8080 mL | 1.6160 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT01772563 | Completed | Drug: volasertib Drug: itraconazole |
Neoplasms | Boehringer Ingelheim | February 4, 2013 | Phase 1 |
| NCT01662505 | Completed | Drug: Volasertib | Leukemia, Myeloid, Acute | Boehringer Ingelheim | August 2012 | Phase 1 |
| NCT02201329 | Completed | Drug: Azacitidine Drug: Volasertib |
Myelodysplastic Syndromes Leukemia, Myelomonocytic, Chronic |
Boehringer Ingelheim | August 2014 | Phase 1 |
| NCT00969553 | Completed | Drug: BI 6727 | Neoplasms | Boehringer Ingelheim | August 2009 | Phase 1 |
| NCT01145885 | Completed | Drug: BI 6727 | Neoplasms | Boehringer Ingelheim | June 2010 | Phase 1 |
 Volasertib inhibits the growth of cervical cancer cellsin vitro.Am J Cancer Res.2015 Nov 15;5(12):3548-59. |
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 Volasertib induces cell cycle arrest at G2/M Phase in cervical cancer cells.Am J Cancer Res.2015 Nov 15;5(12):3548-59. |
 Volasertib induces apoptosis in cervical cancer cells.Am J Cancer Res.2015 Nov 15;5(12):3548-59. |
 Volasertib induces ROS accumulation in cervical cancer cells.
Volasertib potentiates the activity of cisplatin to inhibit the growth of cervical cancer cellsin vitro.Am J Cancer Res.2015 Nov 15;5(12):3548-59. |
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 Inhibition of ROS partially rescues volasertib-induces apoptosis in cervical cancer cells.Am J Cancer Res.2015 Nov 15;5(12):3548-59. |
 Volasertib potentiates the activity of cisplatin to inhibit xenograft tumor growth of cervical cancer cells in nude mice.Am J Cancer Res.2015 Nov 15;5(12):3548-59. |
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