BI 2536

BI2536は、0.83nMのIC50による強力なポロのようなキナーゼ1(Plk1)阻害剤です。

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BI 2536 化学構造
分子量: 521.66

品質と確認

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Quality Control & MSDS

製品情報

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  • 研究分野
  • BI 2536のメカニズム

製品の説明

生物活性

情報 BI2536は、0.83nMのIC50による強力なポロのようなキナーゼ1(Plk1)阻害剤です。
目標 Plk1
IC50 0.83 nM [1]
In vitro試験 BI 2536 blocks the activities of Plk2 and Plk3 to a slightly lesser extent with IC50 of 3.5 nM and 9.0 nM, respectively. In HeLa cells, BI 2536 treatment ranging from 10-100 nM leads to the blocking of the recruitment of γ-tubulin and phosphorylation of Apc6 at mitotic centrosomes, inhibition of cohesin release from chromosome arms, induction of monopolar spindles, as well as a range of other mitotic processes that are known to depend on Plk1. BI 2536 treatment leads to the HeLa cells arrested in G2/M, subsequently a sub-G1 DNA peak indicative of DNA breakdown and apoptosis, and accumulated cleaved PARP p85 fragments in a concentration-dependent manner. BI 2536 inhibits the growth of a panel of 32 human cancer cell lines with EC50 of 2-25 nM, while blocking the proliferation of exponentially growing hTERT-RPE1, human umbilical vein endothelial cells (HUVECs), and normal rat kidney (NRK) cells with EC50 of 12-31 nM. [1] Plk1 inhibition by BI 2536 reduces the growth and viability of anaplastic thyroid carcinoma (ATC) cells such as CAL62, OCUT-1, SW1736, 8505C, and ACT-1 with EC50 values of 1.4-5.6 nM. [2]
In vivo試験 BI 2536 given i.v. once or twice per week is highly efficacious in diverse xenograft models with acceptable tolerability by inhibiting cell proliferation through a mitotic arrest, and subsequently induction of tumor-cell death. Administration of BI 2536 at 50 mg/kg once or twice per week significantly inhibits growth of HCT 116 xenografts with T/C of 15% and 0.3%, respectively. BI 2536 treatment twice-weekly also leads to excellent tumor-growth in BxPC-3 and A549 models with T/C of 5% and 14%, respectively. [1]
臨床試験 A Phase II study of BI 2536 infusional treatment in patients over 60 years of age with refractory or relapsed acute myeloid leukaemia has been completed.
特集 The first potent and selective Plk1 inhibitor that induces all hallmarks of Plk1 inhibition.

推薦された実験操作 (公開の文献だけ)

キナーゼアッセイ: [1]

Plk1 in vitro kinase assay Recombinant human Plk1 (residues 1-603) is expressed as N-terminal, GST-tagged fusion protein with a baculoviral expression system and purified by affinity chromatography with Glutathione-agarose. Enzyme activity assays for Plk1 are performed in the presence of serially diluted BI 2536 with 20 ng of recombinant kinase and 10 μg casein from bovine milk as the substrate. Kinase reactions are performed 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 mM ATP, 0.3 μCi γ-33P-ATP). Reactions are terminated by the addition of 125 μL of ice-cold 5% TCA. After transfer of the precipitates to Multi-Screen mixed ester cellulose filter plates, plates are washed with 1% TCA and quantified radiometrically. Dose-response curve is used for calculating IC50 value.

細胞アッセイ: [1]

細胞系 HeLa, A43, SKOV-3, HT-29, K562, A549, Saos-2, MCF7, HCT116, COLO 205, Hep G2, Raji and PC-3 cells, etc.
濃度 Dissolved in DMSO, final concentrations ~1 μM
処理時間 24 and 72 hours
方法 Cells are exposed to various concentrations of BI 2536 for 24, and 72 hours. Cell growth is assessed by the measurement of Alamar Blue dye conversion in a fluorescence spectrophotometer. For determining the DNA content of the cultures, 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 (PI) in PBS for 20 minutes at RT. Cell-cycle profiles are determined by flow cytometric analysis.

動物実験: [1]

動物モデル Female BomTac:NMRI-Foxn1nu mice injected subcutaneously with HCT 116, NCI-H460, or A549 cells
製剤 Formulated in hydrochloric acid (0.1 N), and diluted with 0.9% NaCl
投薬量 ~50 mg/kg
管理 Injection i.v. once or twice per week
1

参考

化学情報

Download BI 2536 SDF
分子量 521.66
化学式

C28H39N7O3

CAS No. 755038-02-9
別名 N/A
溶解度 (25°C)
  • DMSO 21 mg/mL
  • 水 <1 mg/mL
  • エタノール 100 mg/mL
保管 2年 -20°C
6月-80°Cin DMSO
化学名 (R)-4-(8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide

研究分野

カスタマーレビュー (10)


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Rating
Source Cancer Res, 2011, 71, 1385-1395. BI 2536 purchased from Selleck
Method Tumor growth assay
Cell Lines NOD/SCID mice
Concentrations 12.5-25 mg/kg
Incubation Time 0-24 d
Results As shown in Figure A,tumor growth was significantly inhibited following administration of the third cycle of BI 2536 therapy. When mice were administered 25 mg/ kg weekly on 2 consecutive days for a total of only 2 cycles, tumor growth was inhibited after the second cycle ( Fig. B)

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Rating
Source Cancer Res, 2011, 71, 1385-1395. BI 2536 purchased from Selleck
Method Tumor growth assay
Cell Lines NOD/SCID mice
Concentrations 12.5 mg/kg
Incubation Time 0-60 d
Results We examined a combination of a low dose of BI 2536 (12.5 mg/kg) with a low dose of irinotecan (10 mg/kg), a topoisomerase inhibitor with demonstrated activity in phase II clinical trials in relapsed NB. Single-agent treatment with low-dose of either BI 2536 or irinotecan was comparably efficacious, resulting in significant growth inhibition, as compared with vehicle-treated animals.

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Rating
Source J Biomol Screen, 2013, 18(1), 54-66. BI 2536 purchased from Selleck
Method 3D Tumor Growth Assay
Cell Lines PC-3M cells
Concentrations 0-10uM
Incubation Time 7 d
Results Reduction of colony size was observed for a number of established anticancer drugs, and IC 50 values for those reference compounds were determined based on the average area size of the cluster. IC 50 values were determined in two independent experiments and were quite reproducible.

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Rating
Source J Biomol Screen, 2013, 18(1), 54-66. BI 2536 purchased from Selleck
Method 3D Tumor Growth Assay
Cell Lines PC-3M cells
Concentrations 10uM
Incubation Time 7 d
Results Reduction of colony size was observed for a number of established anticancer drugs, and IC 50 values for those reference compounds were determined based on the average area size of the cluster. IC 50 values were determined in two independent experiments and were quite reproducible.

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Rating
Source J Biol Chem, 2012, 287(21), 17088-99.. BI 2536 purchased from Selleck
Method Cell death assay
Cell Lines HeLa cells
Concentrations 0 -120 nM
Incubation Time 72 h
Results In HeLa cells lacking GRK5, there was an~4.5-fold decrease in the EC50 of BI 2536-mediated cell death (control shRNA, 18.9 ?.2 nM; GRK5 shRNA, 4.1?.1 nM, n = 6, p < 0.05) (Fig. A). Similar to BI 2536, cells lacking GRK5 were ~4.5-fold more sensitive to GSK461364 compared with control cells (EC50 for control shRNA cells, 17.0 ?4.4 nM;EC50 for GRK5-shRNA cells, 3.8 ?0.7 nM, n = 4, p < 0.05).

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Rating
Source J Invest Dermatol, 2011, 131, 1886–1895. BI 2536 purchased from Selleck
Method MTT assay
Cell Lines M14 cell lines, WM-115 cell lines
Concentrations 1-20 nM
Incubation Time
Results Specific inhibition of Plk-1 using the commercially available inhibitor BI 2536 led to a dose- and time-dependent decrease in human melanoma cell viability.

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Rating
Source Nat Cell Biol, 2011, 13, 1265-71. BI 2536 purchased from Selleck
Method cold-stable assay, Immunological methods
Cell Lines RPE1 cells
Concentrations 40 nM
Incubation Time 45 min
Results To examine whether B56-PP2A attenuates the signalling of kinetochore kinases other than Aurora B, we examined Plk1. Remarkably, wash-in of the Plk1 inhibitor BI2536 also restored K-fibres in B56-PP2A-siRNA cells.

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Rating
Source Cancer Cell , 2010, 18, 641–654. BI 2536 purchased from Selleck
Method Immunohistochemical analysis
Cell Lines SCID mice
Concentrations
Incubation Time
Results Control tumors grow exponentially, whereas genetic ablation of Cdc20 results in complete tumor regression in about 10 days. In comparison, treatment with taxol, vincristine, and BI2536 only induces partial responses ( Figure C). In agreement with the data observed in vitro, immunohistochemical analysis of samples taken 3 days after the first treatment indicates lack of proliferation (as measured by BrdU incorporation) and massive apoptosis in Cdc20 null cells, whereas all other samples maintain significant levels of proliferation and reduced apoptotic markers ( Figure D)

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Rating
Source Cancer Res, 2011, 71, 1385-1395. BI 2536 purchased from Selleck
Method Western blot
Cell Lines NB TICs
Concentrations 10-100 nM
Incubation Time 16/24 h
Results The cyclin-dependent kinase inhibitor p21, a newly identified substrate of PLK1, also accumulated in BI 2536-treated NB TICs (Fig. C). Finally, PLK1 kinase activity was inhibited following treatment of NB TICs with BI 2536, as demonstrated by anti-PLK1 immunoprecipitiation followed by in vitro PLK1 kinase assay ( Fig. D)

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Rating
Source Cancer Res, 2011, 71, 1385-1395. BI 2536 purchased from Selleck
Method Trypan blue exclusion, Western blot
Cell Lines NB TICs
Concentrations 10/30/100 nmol/L
Incubation Time 24/48/72 h
Results We observed a significant difference in viable cell numbers in BI2536-treated samples, as compared with DMSO (vehicle)-treated cells, at 24 hours posttreatment. The difference became more pronounced with time, such that at 72 hours there were only approximately 20% viable cells following treatment with 10 nmol/L BI 2536 and approximately 2% to 5% viable cells following treatment with 30 and 100 nmol/L as compared with DMSO-treated cells(Fig. A). At 24 hours, BI 2536-treated cells gradually accumulated cleaved PARP, in contrast to DMSO-treated cells, suggesting induction of apoptosis ( Fig. B).

製品表彰状 (22)

  • Systematic discovery of TLR signaling components delineates viral-sensing circuits. [Chevrier N, et al. Cell 2011;4(10):1087-96]

    PubMed: 22078882
  • Targeting mitotic exit leads to tumor regression in vivo: modulation by Cdk1, Mastl, and the PP2A/B55α,δ phosphatase. [Manchado E, et al. Cancer Cell 2010;18(6):641-54]

    PubMed: 21156286
  • Formation of stable attachments between kinetochores and microtubules depends on the B56-PP2A phosphatase. [Foley EA, et al. Nat Cell Biol 2011;13(10):1265-71]

    PubMed: 21874008
  • SLAIN2 links microtubule plus end-tracking proteins and controls microtubule growth in interphase. [van der Vaart B, et al. J Cell Biol 2011;193(6):1083-99]

    PubMed: 21646404
  • Interphase cytofission maintains genomic integrity of human cells after failed cytokinesis. [Choudhary A, et al. Proc Natl Acad Sci U S A 2013;110(32):13026-31]

    PubMed: 23878225
  • CDK1 phosphorylation of YAP promotes mitotic defects and cell motility and is essential for neoplastic transormation. [Yang S, et al. Cancer Res 2013;73(22):6722-33]

    PubMed: 24101154
  • Small molecule kinase inhibitor screen identifies polo-like kinase 1 as a target for neuroblastoma tumor-initiating cells. [Grinshtein N, et al. Cancer Res 2011;71(4):1385-95]

    PubMed: 21303981
  • Targeting Sonic Hedgehog-Associated Medulloblastoma through Inhibition of Aurora and Polo-like Kinases. [Markant SL, et al. Cancer Res 2013;73(20):6310-22]

    PubMed: 24067506
  • Small RNA sequencing and functional characterization reveals microRNA-143 tumor suppressor activity in liposarcoma. [Ugras S, et al. Cancer Res 2011;71(17):5659-69]

    PubMed: 21693658
  • p21Waf1/Cip1 deficiency causes multiple mitotic defects in tumor cells. [Kreis NN, et al. Oncogene 2013;10.1038/onc.2013.518]

    PubMed: 24317508
  • Integrative mRNA profiling comparing cultured primary cells with clinical samples reveals PLK1 and C20orf20 as therapeutic targets in cutaneous squamous cell carcinoma. [Watt SA, et al. Oncogene 2011;30(46):4666-77]

    PubMed: 21602893
  • Polo-like kinase 1 is a potential therapeutic target in human melanoma. [Jalili A, et al. J Invest Dermatol 2011;131(9):1886-95]

    PubMed: 21654832
  • An RNAi-based screen reveals PLK1, CDK1 and NDC80 as potential therapeutic targets in malignant pleural mesothelioma. [Linton A, et al. Br J Cancer 2013;110(2):510-9]

    PubMed: 24327015
  • An RNAi-based screen reveals PLK1, CDK1 and NDC80 as potential therapeutic targets in malignant pleural mesothelioma. [Linton A, et al. Br J Cancer 2013;10.1038/bjc.2013.731]

    PubMed: 24327015
  • Centrosomal Protein 55 (Cep55) Stability Is Negatively Regulated by p53 Protein through Polo-like Kinase 1 (Plk1). [Chang YC, et al. J Biol Chem 2012;287(6):4376-85]

    PubMed: 22184120
  • G protein-coupled receptor kinase 5 phosphorylates nucleophosmin and regulates cell sensitivity to polo-like kinase 1 inhibition. [So CH, et al. J Biol Chem 2012;287(21):17088-99]

    PubMed: 22467873
  • Induction of mitotic cell death by overriding G2/M checkpoint in endometrial cancer cells with non-functional p53. [Meng X, et al. Gynecol Oncol 2013;128(3):461-9]

    PubMed: 23146687
  • A high-content small molecule screen identifies sensitivity of glioblastoma stem cells to inhibition of polo-like kinase 1. [Danovi D, et al. PLoS One 2013;8(10):e77053]

    PubMed: 24204733
  • The Centrosomal Kinase Plk1 Localizes to the Transition Zone of Primary Cilia and Induces Phosphorylation of Nephrocystin-1. [Seeger-Nukpezah T, et al. PLoS One 2012;7(6):e38838]

    PubMed: 22701722
  • Tools to discriminate between targets of CK2 vs PLK2/PLK3 acidophilic kinases. [Salvi M, et al. Biotechniques 2012;10.2144/000113866]

    PubMed: 23066668
  • Translation of a Tumor Microenvironment Mimicking 3D Tumor Growth Co-culture Assay Platform to High-Content Screening. [Krausz E, et al. J Biomol Screen 2013;18(1):54-66]

    PubMed: 22923784
  • BUBR1 recruits PP2A via the B56 family of targeting subunits to promote chromosome congression. [Peng Xu, et al. Biology Open 2013;2(5):479-86]

    PubMed: 23789096

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