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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).
Physicochemical Properties
| Molecular Formula | C34H50N8O3 |
| Molecular Weight | 618.81 |
| Exact Mass | 618.4 |
| Elemental Analysis | C, 65.99; H, 8.14; N, 18.11; O, 7.76 |
| CAS # | 755038-65-4 |
| Related CAS # | Volasertib trihydrochloride;946161-17-7 |
| PubChem CID | 10461508 |
| Appearance | White to off-white solid powder |
| Density | 1.3±0.1 g/cm3 |
| Index of Refraction | 1.631 |
| LogP | 2.44 |
| 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 |
| Synonyms | BI6727; BI 6727; BI-6727; Volasertib |
| HS Tariff Code | 2934.99.9001 |
| 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) |
Biological Activity
| Targets | PLK1 (IC50 = 0.87 nM); PLK2 (IC50 = 5 nM); PLK3 (IC50 = 56 nM) | |
| ln Vitro |
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| ln Vivo |
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| 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. | |
| 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. | |
| 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 |
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| References |
[1]. Clin Cancer Res . 2009 May 1;15(9):3094-102. [2]. Cancer Res . 2011 Feb 15;71(4):1385-95. [3]. BMC Cancer . 2012 Mar 5:12:80. |
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| Additional Infomation |
Volasertib is a member of the class of pteridines that is (7R)-7-ethyl-5-methyl-8-(propan-2-yl)-7,8-dihydropteridin-6(5H)-one substituted by a [4-({trans-4-[4-(cyclopropylmethyl)piperazin-1-yl]cyclohexyl}carbamoyl)-2-methoxyphenyl]amino group at position 2. It is as polo-like kinase 1 inhibitor (IC50 = 0.87 nM) with potential antineoplastic activity. It has a role as an antineoplastic agent, an apoptosis inducer and an EC 2.7.11.21 (polo kinase) inhibitor. It is a member of cyclopropanes, a member of piperazines, a member of benzamides, a monomethoxybenzene, a substituted aniline, a member of pteridines, a secondary carboxamide, a tertiary amino compound and a secondary amino compound. Volasertib has been used in trials studying the treatment of Leukemia, Neoplasms, Leukemia, Myeloid, Acute, Myelodysplastic Syndromes, and Leukemia, Monocytic, Acute, among others. Volasertib is a dihydropteridinone Polo-like kinase 1 (Plk1) inhibitor with potential antineoplastic activity. Volasertib selectively inhibits Plk1, inducing selective G2/M arrest followed by apoptosis in a variety of tumor cells while causing reversible cell arrest at the G1 and G2 stage without apoptosis in normal cells. Plk1, named after the polo gene of Drosophila melanogaster, is a serine/threonine protein kinase involved in regulating mitotic spindle function in a non-ATP competitive manner. Drug Indication Treatment of acute myeloid leukaemia |
Solubility Data
| 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. 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. 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 corn oil and mix evenly.. Solubility in Formulation 4: 4% DMSO +Corn oil : 2 mg/mL (Please use freshly prepared in vivo formulations for optimal results.) |
| 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 |