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 M4nJSmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MnG2O|IhcA>? MUXJR|UxRTF5MNMxOVEhdk1? M4HPR|I2PTd4MEe0
KG-1 NX71R|A3T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MXu3NkBp NFfiU5dKSzVyPUG1NOKyPjdibl2= MkjyNlU2PzZyN{S=
MOLM-13 MVjHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M2ew[lczKGh? NWHZU|l4UUN3ME21O:KyPDRibl2= NH3zb2QzPTV5NkC3OC=>
MV-4-11 M3GwdWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NIDodZk4OiCq NVnNdIN4UUN3ME2xOuKyPiCwTR?= M4\NSFI2PTd4MEe0
NOMO-1 NG\o[XJIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MmPZO|IhcA>? MVfJR|UxRTF2NdMxO{BvVQ>? M3fRdlI2PTd4MEe0
OCI-AML3 MX\Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MV63NkBp NXPWT5ZCUUN3ME25NOKyPTFibl2= NIH6VZEzPTV5NkC3OC=>
SKM-1 NFz0c5BIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NVLmfWZXPzJiaB?= M{D1bWlEPTB;OUZCtVUzKG6P M1TXNlI2PTd4MEe0
THP-1 NFrBOnJIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MkXoO|IhcA>? Mm\vTWM2OD13NtMxN|khdk1? MVuyOVU4PjB5NB?=
MCF7/LTED  MnzUS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NH;MTogzNjVvNECgcm0> Mlm0OUBl NFvyXYVqdmirYnn0d{Bk\WyuIHfyc5d1cCCrbjDhJIRwe2VvZHXw[Y5l\W62IH3hco5meg>? M{[wTlI2PDhyOUSz
HCC1428/LTED MY\Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NVPSXoRHOi53LUSwJI5O NFTVZo82KGR? Mn\wbY5pcWKrdIOgZ4VtdCCpcn;3eIghcW5iYTDkc5NmNWSncHXu[IVvfCCvYX7u[ZI> NHS3PGkzPTR6MEm0Ny=>
A431 M1PTN2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M1vMUVAuOzBibl2= Mn63NU01KGR? NHLsPYRqdmirYnn0d{Bk\WyuIHfyc5d1cCCrbjDic5RpKGSxc3WtJIFv\CC2aX3lMYRmeGWwZHXueEBu[W6wZYK= M4O2SFI{QDlzMEm2
FaDu  MXTHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M3vhZVAuOTByMDDuUS=> MoH3NU01KGR? NX\vXoc{cW6qaXLpeJMh[2WubDDndo94fGhiaX6gZo91cCCmb4PlMUBidmRidHnt[U1l\XCnbnTlcpQhdWGwbnXy MYmyN|g6OTB7Nh?=
SF188 NUXxRZhNT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M4j2W|UxNTF3MDDuUS=> MlPUO|IhcA>? NHHsWmlFVVOR MVvpcohq[mm2czDj[YxtKHC{b3zp[oVz[XSrb36= MYOyN|g5PzZ2NR?=
T98G M4Lnfmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MWq1NE0yPTBibl2= NEDqclU4OiCq M2OyWmROW09? M1zwcolvcGmkaYTzJINmdGxicILvcIln\XKjdHnvci=> NFjJV4czOzh6N{[0OS=>
DU145 NV3hfZRST3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NYLU[3pNOTBxNUCvNlUxKG6P MmiyNlQhcA>? MX7JR|UxRDFyIH7N Mn3sNlM5QDR2Mki=
LNCaP NUDlS21KT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M1PzeFExNzVyL{K1NEBvVQ>? MW[yOEBp M{W5XGlEPTB:MUCgcm0> Mn\CNlM5QDR2Mki=
PC3 MlXSS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NFXvZYMyOC93MD:yOVAhdk1? MXeyOEBp MlrTTWM2OOLKvE[wNEBvVQ>? NH\ibmszOzh6NESyPC=>
RT4 M2nD[Gdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MY[0PEBp M3e1RWlEPTB;MUGxMlI4KG6P MUSyN|c6OjZ|OR?=
5637 M4[yU2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MUS0PEBp MYPJR|UxRTFzNkWuNVQhdk1? NVHJOpZbOjN5OUK2N|k>
T24 M3nTNmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MXi0PEBp NVLvUm1iUUN3ME2yNFQvQTFibl2= MUSyN|c6OjZ|OR?=
KMCH-1 MUfBdI9xfG:|aYOgRZN{[Xl? NGr4ZnYzODBibl2= NGrHV3YzPCCq NYfpOZZFcW6mdXPld{BieG:ydH;zbZM> MkHGNlM4ODN4N{O=
Mz-ChA-1 NH7NV|lCeG:ydH;zbZMhSXO|YYm= MmnQNlAxKG6P NWPyTJZ[OjRiaB?= M4D2b4lv\HWlZYOgZZBweHSxc3nz MmLnNlM4ODN4N{O=
HUCCT-1 M{TMNmFxd3C2b4Ppd{BCe3OjeR?= MYiyNFAhdk1? M3TGdVI1KGh? MnqwbY5lfWOnczDhdI9xfG:|aYO= MVeyN|cxOzZ5Mx?=
HCT 116 MnnNS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NUf4PZZITUN3MNMgQUAzOyCwTR?= MYCxPVM5Ozh{Mx?=
NCI-H460 M4HGbWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NULydW1PTUN3MNMgQUAzOSCwTR?= MkfYNVk{QDN6MkO=
BRO NE\zb2RIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NUfrfYs3TUN3MNMgQUAyOSCwTR?= MVGxPVM5Ozh{Mx?=
GRANTA-519 MnywS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MUPFR|UxyqB;IEG1JI5O M4LHUFE6Ozh|OEKz
HL-60 NV;sZmdQT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NEXNTXBGSzVywrC9JFMzKG6P NILsVlAyQTN6M{iyNy=>
THP-1 MXHHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M4TYc2VEPTBiPTCzOkBvVQ>? Mo\uNVk{QDN6MkO=
Raji MnfpS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MV3FR|UxKD1iM{egcm0> NVLY[ZVkOTl|OEO4NlM>

... 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 3年-20℃
2年-80℃in solvent
別名 N/A
溶解度 (25°C) * In vitro DMSO 20 mg/mL warming (32.32 mM)
Water <1 mg/mL
Ethanol <1 mg/mL
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

文献中の引用 (10)

Frequently Asked Questions

  • Question 1
    I wonder how to reconstitute the inhibitor for in vivo studies?

    Answer: Volasertib can be dissolved in 4% DMSO+Corn oil at 2mg/ml for i.p. injection in mice. For oral administration, it can be formulated in hydrochloric acid (0.1 N), and diluted with 0.9% NaCl, or suspended in 0.5% Natrosol 250 hydroxyethyl-cellulose as indicated in the publications. We also suggest the vehicle 30% PEG400/0.5% Tween80/5% propylene glycol for a suspension which we tested in house.

技術サポート&よくある質問(FAQ)

ストックの作り方、阻害剤の保管する方法、細胞実験や動物実験に注意すべきな点を全部含めており、製品を取扱う時よくあった質問に対して取扱説明書でお答えいたします。

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
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