| Description |
BI 2536 is a potent Plk1 inhibitor with IC50 of 0.83 nM. |
| Targets |
Plk1 |
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| IC50 |
0.83 nM [1] |
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| In vitro |
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 |
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] |
| Clinical Trials |
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. |
| Features |
BI 2536 is the first potent and selective Plk1 inhibitor that induces all hallmarks of Plk1 inhibition. |
| Cell lines |
HeLa, A43, SKOV-3, HT-29, K562, A549, Saos-2, MCF7, HCT116, COLO 205, Hep G2, Raji and PC-3 cells, etc. |
| Concentrations |
Dissolved in DMSO, final concentrations ~1 μM |
| Incubation Time |
24 and 72 hours |
| Method |
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. |
Systematic discovery of TLR signaling components delineates viral-sensing circuits. [Chevrier N, et al. Cell, 2011, 147(4), 853-867]
PubMed: 22078882Targeting 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), 641-654]
PubMed: 21156286Formation of stable attachments between kinetochores and microtubules depends on the B56-PP2A phosphatase. [Foley EA, et al. Nat Cell Biol, 2011, 13(10), 1265-1271]
PubMed: 21874008SLAIN2 links microtubule plus end-tracking proteins and controls microtubule growth in interphase. [van der Vaart B, et al. J Cell Biol, 2011, 193(6), 1083-1099]
PubMed: 21646404Small 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), 1385-1395]
PubMed: 21303981Small RNA sequencing and functional characterization reveals microRNA-143 tumor suppressor activity in liposarcoma. [Ugras S, et al. Cancer Res, 2011, 71(17), 5659-5669]
PubMed: 21693658Integrative 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), 4666-4677]
PubMed: 21602893Polo-like kinase 1 is a potential therapeutic target in human melanoma. [Jalili A, et al. J Invest Dermatol, 2011, 131(9), 1886-1895]
PubMed: 21654832Centrosomal 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: 22184120G 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: 22467873The 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: 22701722Induction 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: 23146687Tools to discriminate between targets of CK2 vs PLK2/PLK3 acidophilic kinases. [Salvi M, et al. Biotechniques, 2012, ]
PubMed: 23066668Translation 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
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