您当前所在的位置:首页 > 产品中心 > 产品信息
BI6727_分子结构_CAS_755038-65-4)
点击图片或这里关闭

BI6727

产品号 S2235 公司名称 Selleck Chemicals
CAS号 755038-65-4 公司网站 http://www.selleckchem.com
分子式 C34H50N8O3 电 话 (877) 796-6397
分子量 618.8126 传 真 (832) 582-8590
纯 度 电子邮件 sales@selleckchem.com
保 存 -20°C Chembase数据库ID: 73084

产品价格信息

请登录

产品别名

标题
BI6727
IUPAC标准名
4-{[(7R)-7-ethyl-5-methyl-6-oxo-8-(propan-2-yl)-5,6,7,8-tetrahydropteridin-2-yl]amino}-3-methoxy-N-[(1r,4r)-4-[4-(cyclopropylmethyl)piperazin-1-yl]cyclohexyl]benzamide
IUPAC传统名
4-{[(7R)-7-ethyl-8-isopropyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino}-3-methoxy-N-[(1r,4r)-4-[4-(cyclopropylmethyl)piperazin-1-yl]cyclohexyl]benzamide
别名
Volasertib

产品登记号

CAS号 755038-65-4

产品性质

作用靶点 PLK
成盐信息 Free Base
保存条件 -20°C

产品详细信息

详细说明 (English)
Research Area
Description Caner
Biological Activity
Description BI6727 (Volasertib) is a highly potent Plk1 inhibitor with IC50 of 0.87 nM.
Targets Plk1
IC50 0.87 nM [1]
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]
Clinical Trials A Phase I study of BI6727 in Japanese patients with advanced solid tumors is currently ongoing.
Features BI6727 has a high volume of distribution, indicating good tissue penetration, and a long terminal half-life.
Combination Therapy
Description A Phase I study of BI6727 in combination with oral BIBW 2992 (Afatinib) in patients with advanced solid tumors is currently ongoing.
Protocol
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
Methods 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
Doses ~25 mg/kg/day
Administration Injected i.v., or given intragastrally via gavage needle
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.
[3] Harris PS, et al. BMC Cancer, 2012, 12, 80.