| Size | Price | |
|---|---|---|
| 500mg | ||
| 1g | ||
| Other Sizes |
| Targets |
- 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] PLK1 0.87 nM (IC50); PLK2 5 nM (IC50); PLK3 56 nM (IC50) |
|---|---|
| ln Vitro |
In numerous cell lines, volasertib trihydrochloride (BI 6727 trihydrochloride; 0.01-10000 nM; 72 hours) shows EC50 values ranging from 11 to 37 nmol/L[1]. Cells with a 4N DNA content accumulate when exposed to volasertib trihydrochloride (10–1000 nM) for 24 hours, which is suggestive of a cell cycle block in the G2-M phase[1]. At 48 hours, volasertib trihydrochloride (100 nM; 24-72 hours) causes cell death[1].
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 |
In human colon cancer xenograft models, volasertib trihydrochloride (BI 6727 trihydrochloride; a total weekly dose of 50 mg/kg; Oral; once a week, twice a week, or daily; for 40 days) exhibits comparable efficacy[1]. In human colon cancer xenograft models, volasertib trihydrochloride (15, 20, or 25 mg/kg/day; iv; 2 consecutive days per week; for 40 days) causes a considerable delay in tumor growth and even tumor regression [1]. kg administered once a week or 10 mg/kg orally;1] markedly inhibits the formation of tumors in a non-small cell lung cancer xenograft model derived from NCI-H460 cells. In HCT 116 tumor-bearing nude mice, volasertib (a single dose of 40 mg/kg; iv) significantly (13-fold) increases the number of mitotic cells[1]. Volasertib exhibits a large terminal half-life (Vss = 22 L/kg, t1/2 = 54 h) and a high volume of distribution in mice (Vss = 7.6 L/kg, t1/2 = 46 h)[1].
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 |
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 |
Cell Proliferation Assay[1]
Cell Types: Multiple cell lines Tested Concentrations: 0.01-10000 nM Incubation Duration: 72 hrs (hours) Experimental Results: Inhibited proliferation of multiple cell lines derived from various cancer tissues, including carcinomas of the colon (HCT 116, EC50=23 nmol/L) and lung (NCI-H460, EC50=21 nmol/L), melanoma (BRO, EC50=11 nmol/L), and hematopoietic cancers (GRANTA-519, EC50 =15 nmol/L; HL-60, EC50=32 nmol/L; THP-1, E50=36 nmol/L and Raji, EC50=37 nmol/L) with EC50 values of 11 to 37 nmol/L. Apoptosis Analysis [1] Cell Types: NCI-H460 cells Tested Concentrations: 100 nM Incubation Duration: 24, 48, 72 hrs (hours) Experimental Results: G2-M arrest at 24 hrs (hours) was followed by induction of apoptosis at 48 hrs (hours). Cell Cycle Analysis[1] Cell Types: NCI-H460 cells Tested Concentrations: 10, 30, 100, 300, 1000 nM Incubation Duration: 24 hrs (hours) Experimental Results: Resulted in accumulation of cells with 4N DNA content, indicative of a cell cycle block in G2-M phase. 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 |
Animal/Disease Models: Female BomTac:NMRI- Foxn1nu (nude) mice (Taconic) were grafted sc with HCT 116 human colon carcinoma cells (ATCC CCL-247)[1]
Doses: A total weekly dose of 50 mg/kg Route of Administration: Oral; once a week, twice a week, or daily; for 40 days Experimental Results: demonstrated comparable efficacy and were well tolerated. Animal/Disease Models: Female BomTac:NMRI-Foxn1nu (nude) mice and male Wistar rats of the strain Crl:WI[1] Doses: 35 mg/kg (mice) or 10 mg/kg (rat) (pharmacokinetic/PK Analysis) Route of Administration: IV 5-minute infusion; a single dose 5-minute infusion Experimental Results: Had high volume of distribution and a long terminal half-life in mice (Vss=7.6 L/kg, t1/2= 46 h) and rats (Vss=22 L/kg, t1/2=54 h). 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] |
| 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]
|
| References |
|
| Additional Infomation |
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 (e.g., Cdc25C, 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 (e.g., BI 2536)[2] |
| Molecular Formula |
C34H53CL3N8O3
|
|---|---|
| Molecular Weight |
728.20
|
| Exact Mass |
726.331
|
| Elemental Analysis |
C, 56.08; H, 7.34; Cl, 14.60; N, 15.39; O, 6.59
|
| CAS # |
946161-17-7
|
| Related CAS # |
Volasertib;755038-65-4; 946161-18-8 (HCl hydrate); 946161-17-7 (HCl)
|
| PubChem CID |
16718566
|
| Appearance |
Typically exists as solid at room temperature
|
| LogP |
7.326
|
| Hydrogen Bond Donor Count |
5
|
| Hydrogen Bond Acceptor Count |
9
|
| Rotatable Bond Count |
10
|
| Heavy Atom Count |
48
|
| Complexity |
996
|
| Defined Atom Stereocenter Count |
1
|
| SMILES |
Cl.Cl.Cl.O=C(C1C=CC(=C(C=1)OC)NC1=NC=C2C(=N1)N(C(C)C)[C@@H](C(N2C)=O)CC)NC1CCC(CC1)N1CCN(CC1)CC1CC1
|
| InChi Key |
JFEPFDDQDQBWIL-NGDVEHRBSA-N
|
| InChi Code |
InChI=1S/C34H50N8O3.3ClH/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);3*1H/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;trihydrochloride
|
| 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 |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
|
| Solubility (In Vitro) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
|
|---|---|
| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.3732 mL | 6.8662 mL | 13.7325 mL | |
| 5 mM | 0.2746 mL | 1.3732 mL | 2.7465 mL | |
| 10 mM | 0.1373 mL | 0.6866 mL | 1.3732 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.
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