Volasertib (BI 6727)

Volasertib (BI 6727) is a highly potent Plk1 inhibitor with IC50 of 0.87 nM. It shows 6- and 65-fold greater selectivity against Plk2 and Plk3. Phase 3.

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Volasertib (BI 6727) Chemical Structure

Volasertib (BI 6727) Chemical Structure
Molecular Weight: 618.81

Validation & Quality Control

Customer Reviews(2)

Quality Control & MSDS

Related Compound Libraries

Volasertib (BI 6727) is available in the following compound libraries:

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Product Information

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  • Research Area
  • Volasertib (BI 6727) Mechanism

Product Description

Biological Activity

Description Volasertib (BI 6727) is a highly potent Plk1 inhibitor with IC50 of 0.87 nM. It shows 6- and 65-fold greater selectivity against Plk2 and Plk3. Phase 3.
Targets PLK1 [1]
IC50 0.87 nM
In vitro Like BI2536, BI6727 is an ATP-competitive kinase inhibitor from the dihydropteridinone class of compounds. In addition to Plk1, BI6727 also potently inhibits two closely related kinases Plk2 and Plk3 with IC50 of 5 nM and 56 nM, respectively. BI6727 at concentrations up to 10 μM displays no inhibitory activity against a panel of >50 other kinases. BI6727 inhibits the proliferation of multiple cell lines derived from various cancer tissues, including HCT116, NCI-H460, BRO, GRANTA-519, HL-60, THP-1, and Raji cells with EC50 of 23 nM, 21 nM, 11 nM, 15 nM, 32 nM, 36 nM, and 37 nM, respectively. BI6727 treatment (100 nM) in NCI-H460 cells induces an accumulation of mitotic cells with monopolar spindles and positive staining for histone H3 phosphoserine 10, confirming that cells are arrested early in the M phase, followed by induction of apoptosis. [1] Low nanomolar concentrations of BI6727 display potent inhibitory activity against neuroblastoma (NB) tumor-initiating cells (NB TIC) with EC50 of 21 nM, whereas only micromolar concentrations of BI6727 are cytotoxic for normal pediatric neural stem cells. [2] BI6727 induces growth arrest of Daoy and ONS-76 medulloblastoma cells similar to BI 2536. [3]
In vivo Administration of BI6727 significantly inhibits the growth of multiple human carcinoma xenografts including HCT116, NCI-H460, and taxane-resistant CXB1 colon carcinoma, accompanied by an increase in the mitotic index as well as an increase in apoptosis. [1] In in vivo studies, BI6727 shows better toxicity and pharmacokinetic profile compared to BI2536. [3]
Features A high volume of distribution, indicating good tissue penetration, and a long terminal half-life.

Protocol(Only for Reference)

Kinase Assay: [1]

In vitro kinase assays Recombinant human Plk1 (residues 1-603) is expressed as NH2-terminal, GST-tagged fusion protein using a baculoviral expression system and purified by affinity chromatography using glutathione-agarose. Enzyme activity assays for Plk1 are done in the presence of serially diluted BI6727 using 20 ng of recombinant kinase and 10 μg casein from bovine milk as substrate. Kinase reactions are done in a final volume of 60 μL for 45 minutes at 30 °C [15 mM MgCl2, 25 mM MOPS (pH 7.0), 1 mM DTT, 1% DMSO, 7.5 μM ATP, 0.3 μCi γ-32P-ATP]. Reactions are terminated by the addition of 125 μL of ice-cold 5% TCA. After transferring the precipitates to MultiScreen mixed ester cellulose filter plates, plates are washed with 1% TCA and quantified radiometrically. Dose-response curves are used for calculating IC50 value.

Cell Assay: [1]

Cell lines HCT116, NCI-H460, BRO, GRANTA-519, HL-60, THP-1, and Raji
Concentrations Dissolved in DMSO, final concentrations ~1 μM
Incubation Time 24, 48, and 72 hours
Method Cell proliferation assays are done by incubating cells in the presence of various concentrations of BI6727 for 24, 48, and 72 hours and cell growth is assessed by measuring Alamar blue dye conversion in a fluorescence spectrophotometer. Effective concentrations at which cellular growth is inhibited by 50% (EC50) are extrapolated from the dose-response curve fit. To determine the DNA content, cell suspensions are fixed in 80% ethanol, treated for 5 minutes with 0.25% Triton X-100 in PBS, and incubated with 0.1% RNase and 10 μg/mL propidium iodide in PBS for 20 minutes at room temperature. Cell cycle profiles are determined by flow cytometric analysis.

Animal Study: [1]

Animal Models Female BomTac:NMRI-Foxn1nu mice grafted s.c. with HCT116, NCI-H460, or CXB1 cells
Formulation Formulated in hydrochloric acid (0.1 N), and diluted with 0.9% NaCl, or suspended in 0.5% Natrosol 250 hydroxyethyl-cellulose
Dosages ~25 mg/kg/day
Administration Injected i.v., or given intragastrally via gavage needle
Solubility 30% PEG400/0.5% Tween80/5% propylene glycol, , 30 mg/mL
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesBaboonDogMonkeyRabbitGuinea pigRatHamsterMouse
Weight (kg)121031.80.40.150.080.02
Body Surface Area (m2)0.60.50.240.150.050.0250.020.007
Km factor202012128653
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Rudolph D, et al. Clin Cancer Res, 2009, 15(9), 3094-3102.

[2] Grinshtein N, et al. Cancer Res, 2011, 71(4), 1385-1395.

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Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2014-09-13)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT02198482 Not yet recruiting Acute Myeloid Leukemia (AML) University of Ulm September 2014 Phase 2
NCT02201329 Recruiting Myelodysplastic Syndromes|Leukemia, Myelomonocytic, Chronic Boehringer Ingelheim August 2014 Phase 1
NCT02003573 Recruiting Leukemia, Myeloid, Acute Boehringer Ingelheim January 2014 Phase 1
NCT01957644 Recruiting Myelodysplastic Syndromes|Leukemia, Myelomonocytic, Chronic Boehringer Ingelheim November 2013 Phase 1
NCT01971476 Recruiting Leukemia|Neoplasms Boehringer Ingelheim October 2013 Phase 1

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Chemical Information

Download Volasertib (BI 6727) SDF
Molecular Weight (MW) 618.81
Formula

C34H50N8O3

CAS No. 755038-65-4
Storage 3 years -20℃Powder
6 months-80℃in DMSO
Synonyms
Solubility (25°C) * In vitro DMSO 50 mg/mL (80 mM)
Water <1 mg/mL (<1 mM)
Ethanol 124 mg/mL (200 mM)
In vivo 30% PEG400/0.5% Tween80/5% propylene glycol, 30 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Name N-((1r,4r)-4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexyl)-4-((R)-7-ethyl-8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-ylamino)-3-methoxybenzamide

Research Area

Customer Reviews (2)


Click to enlarge
Rating
Source Dr. Xiangbing Meng from University of Iowa. Volasertib (BI 6727) purchased from Selleck
Method Western blot, MTT assays
Cell Lines Hec50 cells
Concentrations 0-50 nM
Incubation Time 3 d
Results Reduction of Cdc2 Tyr15 phosphorylation and increase Histone H3 Ser10 phosphorylation in cells treated with BI 6727 was observed.

Click to enlarge
Rating
Source Dr. Xiangbing Meng from University of Iowa. Volasertib (BI 6727) purchased from Selleck
Method Flow cytometry
Cell Lines Hec50 cells
Concentrations 10 nM
Incubation Time 24 h
Results Hec50 cells are arrested in mitosis after 24hours treatment with 10nM BI 6727.

Product Citations (3)

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