Volasertib (BI 6727) 化学構造
分子量: 618.81

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製品説明

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製品の説明

生物活性

製品説明 Volasertib (BI 6727)は、0.87nMのIC50による非常に強力なポロのようなキナーゼ1(Plk1)阻害剤です。
ターゲット Plk1
IC50 0.87 nM [1]
In vitro試験 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]
Cell Data
Cell LinesAssay TypeConcentrationIncubation TimeFormulationActivity DescriptionPMID
KASUMI-1 NWfKcJFUT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MUG3NkBp MV3JR|UxRTF5MNMxOVEhdk1? Mn:wNlU2PzZyN{S=
KG-1 Mli5S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MofPO|IhcA>? NVjjbW41UUN3ME2xOVDDuTZ5IH7N M{XBdFI2PTd4MEe0
MOLM-13 Ml[xS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NVLzXIFlPzJiaB?= MkDXTWM2OD13N9MxOFQhdk1? Mn;ENlU2PzZyN{S=
MV-4-11 MXzHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MXu3NkBp MVXJR|UxRTF4wsG2JI5O MYKyOVU4PjB5NB?=
NOMO-1 MVHHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MnvjO|IhcA>? NFjsbnJKSzVyPUG0OeKyPyCwTR?= NVTtZnZjOjV3N{[wO|Q>
OCI-AML3 MXvHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MYq3NkBp MYfJR|UxRTlywsG1NUBvVQ>? NHfYWnMzPTV5NkC3OC=>
SKM-1 NIHoe4tIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NHmwWFg4OiCq M16wVGlEPTB;OUZCtVUzKG6P MX2yOVU4PjB5NB?=
THP-1 NFrIT3BIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NF3xVIo4OiCq NGfoe25KSzVyPUW2xtE{QSCwTR?= NF;0c5IzPTV5NkC3OC=>
MCF7/LTED  NVvyUHU5T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NUfVdolQOi53LUSwJI5O M2XDU|Uh\A>? MX\pcohq[mm2czDj[YxtKGe{b4f0bEBqdiCjIHTvd4Uu\GWyZX7k[Y51KG2jbn7ldi=> NWHuVo9yOjV2OEC5OFM>
HCC1428/LTED MkHiS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NX\IRZQ4Oi53LUSwJI5O NFr2XpI2KGR? M4ToZ4lvcGmkaYTzJINmdGxiZ4Lve5RpKGmwIHGg[I9{\S2mZYDlcoRmdnRibXHucoVz NUH0d5NnOjV2OEC5OFM>
A431 NVXZRYQzT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NFPGS3QxNTNyIH7N M3K2SlEuPCCm M4TuZ4lvcGmkaYTzJINmdGxiZ4Lve5RpKGmwIHLveIgh\G:|ZT2gZY5lKHSrbXWt[IVx\W6mZX70JI1idm6nch?= MYKyN|g6OTB7Nh?=
FaDu  MknOS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NYLuSmEyOC1zMECwJI5O MnzzNU01KGR? MVPpcohq[mm2czDj[YxtKGe{b4f0bEBqdiCkb4ToJIRwe2VvIHHu[EB1cW2nLXTldIVv\GWwdDDtZY5v\XJ? MmPsNlM5QTFyOU[=
SF188 Mn7VS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NYX0dmZnPTBvMUWwJI5O NIfIWXE4OiCq MmXISG1UVw>? MlvybY5pcWKrdIOgZ4VtdCCycn;sbYZmemG2aX;u NWfEfFZGOjN6OEe2OFU>
T98G NIDl[JdIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NVPMeXZjPTBvMUWwJI5O NW\Oe403PzJiaB?= MXvEUXNQ NXq1RpZncW6qaXLpeJMh[2WubDDwdo9tcW[ncnH0bY9v M3nNfFI{QDh5NkS1
DU145 MoTsS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? Mm\rNVAwPTBxMkWwJI5O NGfyRowzPCCq NYnySnBkUUN3MEyxNEBvVQ>? M{TJO|I{QDh2NEK4
LNCaP MX\Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MljQNVAwPTBxMkWwJI5O MY[yOEBp NFnKOnNKSzVyPEGwJI5O M1juc|I{QDh2NEK4
PC3 M17Ncmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NYPLfWo6OTBxNUCvNlUxKG6P NWnoUXZMOjRiaB?= MXjJR|Ux6oj:NkCwJI5O M2LJWlI{QDh2NEK4
RT4 NHz3Wo5Iem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NGnhVWI1QCCq Ml3sTWM2OD1zMUGuNlchdk1? M3LjcFI{Pzl{NkO5
5637 NF7YXGlIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NFjte5I1QCCq MXjJR|UxRTFzNkWuNVQhdk1? MYWyN|c6OjZ|OR?=
T24 NUHuTlVnT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MofUOFghcA>? MnvJTWM2OD1{MESuPVEhdk1? MnrKNlM4QTJ4M{m=
KMCH-1 NV;yO|FTSXCxcITvd4l{KEG|c3H5 Ml3sNlAxKG6P MXyyOEBp NFzMXWJqdmS3Y3XzJIFxd3C2b4Ppdy=> NXvZdYNNOjN5MEO2O|M>
Mz-ChA-1 NYDp[XFsSXCxcITvd4l{KEG|c3H5 NGn0ZVQzODBibl2= NF;DXmwzPCCq MkD0bY5lfWOnczDhdI9xfG:|aYO= Mo\LNlM4ODN4N{O=
HUCCT-1 MYLBdI9xfG:|aYOgRZN{[Xl? MoTGNlAxKG6P MV[yOEBp MkTWbY5lfWOnczDhdI9xfG:|aYO= MY[yN|cxOzZ5Mx?=
HCT 116 MVnHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NWPiXZZvTUN3MNMgQUAzOyCwTR?= NUnUO4hROTl|OEO4NlM>
NCI-H460 NYfVZo0xT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MmfhSWM2OMLiPTCyNUBvVQ>? MlrVNVk{QDN6MkO=
BRO NH7BdIJIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MYTFR|UxyqB;IEGxJI5O M{Lm[lE6Ozh|OEKz
GRANTA-519 NWPaNINnT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NUTQWGtKTUN3MNMgQUAyPSCwTR?= M17hUVE6Ozh|OEKz
HL-60 MmPvS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M3jNRmVEPTEEoE2gN|Ihdk1? NVzUSm5YOTl|OEO4NlM>
THP-1 NHrtPXhIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MX\FR|UxKD1iM{[gcm0> NFnVPJYyQTN6M{iyNy=>
Raji NHXXb21Iem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NILZbZdGSzVyIE2gN|chdk1? M3uxVFE6Ozh|OEKz

... Click to View More Cell Line Experimental Data

In vivo試験 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]
臨床試験 A Phase I study of BI6727 in Japanese patients with advanced solid tumors is currently ongoing.
特集 A high volume of distribution, indicating good tissue penetration, and a long terminal half-life.

プロトコル (参考用のみ)

キナーゼアッセイ: [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.

細胞アッセイ: [1]

細胞株 HCT116, NCI-H460, BRO, GRANTA-519, HL-60, THP-1, and Raji
濃度 Dissolved in DMSO, final concentrations ~1 μM
反応時間 24, 48, and 72 hours
実験の流れ 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.

動物実験: [1]

動物モデル Female BomTac:NMRI-Foxn1nu mice grafted s.c. with HCT116, NCI-H460, or CXB1 cells
製剤 Formulated in hydrochloric acid (0.1 N), and diluted with 0.9% NaCl, or suspended in 0.5% Natrosol 250 hydroxyethyl-cellulose
投薬量 ~25 mg/kg/day
投与方法 Injected i.v., or given intragastrally via gavage needle

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

SpeciesMouseRatRabbitGuinea pigHamsterDogMonkeyBaboon
Weight (kg)0.020.151.80.40.0810312
Body Surface Area (m2)0.0070.0250.150.050.020.50.240.6
Km factor361285201220
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

参考

化学情報

Download Volasertib (BI 6727) SDF
分子量 618.81
化学式

C34H50N8O3

CAS No. 755038-65-4
保管 2年-20℃
6月-80℃in solvent
別名 N/A
溶解度 (25°C) * In vitro DMSO 20 mg/mL warming (32.32 mM)
<1 mg/mL (<1 mM)
エタノール <1 mg/mL (<1 mM)
In vivo 4% DMSO+corn oil 2mg/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.
化学名 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

カスタマーフィードバック (3)


Click to enlarge
Rating
Source Oncogene, 2013, 10.1038/onc.2013.518. Volasertib (BI 6727) purchased from Selleck
Method Western blot
Cell Lines HeLa, MCF-7 cells
Concentrations 50 nM
Incubation Time 16 h
Results Moreover, HeLa and MCF7 cells treated with antimitotic agents, like paclitaxel, Polo-like kinase 1 (Plk1) inhibitor BI 2536 or BI 6727, exhibited the phosphorylated p21 bands in mitosis. BI 6727 decreased p21 in HeLa cells. p21 is abundantly present in mitosis, in particular, when mitotic cells face stress.

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.

文献中の引用 (10)

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
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