BI 2536

Plk1 inhibitor,potent and ATP-competitive CAS# 755038-02-9

BI 2536

Catalog No. BCC2081----Order now to get a substantial discount!

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Quality Control of BI 2536

Number of papers citing our products

Chemical structure

BI 2536

3D structure

Chemical Properties of BI 2536

Cas No. 755038-02-9 SDF Download SDF
PubChem ID 11364421 Appearance Powder
Formula C28H39N7O3 M.Wt 521.67
Type of Compound N/A Storage Desiccate at -20°C
Solubility DMSO : ≥ 55.5 mg/mL (106.39 mM)
*"≥" means soluble, but saturation unknown.
Chemical Name 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide
SMILES CCC1C(=O)N(C2=CN=C(N=C2N1C3CCCC3)NC4=C(C=C(C=C4)C(=O)NC5CCN(CC5)C)OC)C
Standard InChIKey XQVVPGYIWAGRNI-JOCHJYFZSA-N
Standard InChI InChI=1S/C28H39N7O3/c1-5-22-27(37)34(3)23-17-29-28(32-25(23)35(22)20-8-6-7-9-20)31-21-11-10-18(16-24(21)38-4)26(36)30-19-12-14-33(2)15-13-19/h10-11,16-17,19-20,22H,5-9,12-15H2,1-4H3,(H,30,36)(H,29,31,32)/t22-/m1/s1
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of BI 2536

DescriptionBI2536 is a potent inhibitor of Plk1 with IC50 of 0.83 nM.
TargetsPlk1    
IC500.83 nM     

Protocol

Cell experiment: [1]

Cell lines

HeLa-S3 cells

Preparation method

The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while.Stock solution can be stored below -20°C for several months.

Reacting condition

1 μM, 24 hours

Applications

The effect of BI 2536 on the cell-cycle profile of cancer cells grown in vitro was assessed by immunofluorescence microscopy and flow cytometry. BI2536 caused HeLa cells to accumulate with a 4N DNA content, indicative of a cell-cycle block in either G2 phase or mitosis. The mitotic figures observed in BI 2536-treated cultures of HeLa cells displayed abnormal mitotic figures at EC50 values closely matching the induction of a G2/M arrest.

Animal experiment: [1]

Animal models

Immunodeficient nu/nu mice injected with HCT 116 cells

Dosage form

Intravenous injection, 40–50mg/kg, once or twice per week

Application

The administration of BI 2536 was found to be highly efficacious in diverse xenograft models, such as the HCT 116 colon cancer with complete tumor suppression with the twice per week schedule and a T/C value of 16% with once per week treatment. By using a more rigorous model of larger HCT 116 tumors, in which treatment was delayed until cancer nodules reached a median size of 500 mm3, it was found that five cycles of BI 2536 induced marked tumor regressions, whereas the control mice showed progressive disease.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

References:

[1] Steegmaier M, Hoffmann M, Baum A, et al. BI 2536, a potent and selective inhibitor of polo-like kinase 1, inhibits tumor growth in vivo. Current Biology, 2007, 17(4): 316-322.

BI 2536 Dilution Calculator

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BI 2536 Molarity Calculator

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Preparing Stock Solutions of BI 2536

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 1.9169 mL 9.5846 mL 19.1692 mL 38.3384 mL 47.923 mL
5 mM 0.3834 mL 1.9169 mL 3.8338 mL 7.6677 mL 9.5846 mL
10 mM 0.1917 mL 0.9585 mL 1.9169 mL 3.8338 mL 4.7923 mL
50 mM 0.0383 mL 0.1917 mL 0.3834 mL 0.7668 mL 0.9585 mL
100 mM 0.0192 mL 0.0958 mL 0.1917 mL 0.3834 mL 0.4792 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

Research Update of BI 2536

1. Human ABCB1 (P-glycoprotein) and ABCG2 mediate resistance to BI 2536, a potent and selective inhibitor of Polo-like kinase 1. Biochem Pharmacol. 2013 Oct 1;86(7):904-13. doi: 10.1016/j.bcp.2013.08.004. Epub 2013 Aug 17.
Abstract
BI 2536, a Plk1 inhibitor, exhibits antiproliferative activity against cancer cells through promoting G2/M cell cycle arrest. Acquired BI 2536 resistance in ABCB1 or ABCB2 overexpressing human cancer cells is caused by BI 2536 induced inhibition of drug substrate transport mediated by ABC transporters and can be diminished by addition of inhibitors of ABC transporters.
2. A phase I open-label dose-escalation study of intravenous BI 2536 together with pemetrexed in previously treated patients with non-small-cell lung cancer. Clin Lung Cancer. 2013 Jan;14(1):19-27. doi: 10.1016/j.cllc.2012.04.003. Epub 2012 Jun 1.
Abstract
The combination of BI 2536, a PlK1 inhibitor, and pemetrexed was evaluated for MTD, safety, efficacy and PK in previously treated advanced or metastatic non-small-cell lung cancer.
3. A randomized, open-label, phase I/II trial to investigate the maximum tolerated dose of the Polo-like kinase inhibitor BI 2536 in elderly patients with refractory/relapsed acute myeloid leukaemia. Br J Haematol. 2013 Oct;163(2):214-22. doi: 10.1111/bjh.12518. Epub 2013 Aug 16.
Abstract
BI 2536, a Plk inhibitor capable of inducing mitotic arrest and apoptosis, showed modest clinical activity (9% response rate) in elderly patients with relapsed/refractory AML, which increased bone marrow cells in G2/M with a characteristic pattern of mitotic catastrophe and caused haematological side effects.
4. PLK1 expression and BI 2536 effects in childhood acute lymphoblastic leukemia. Pediatr Blood Cancer. 2014 Feb 12. doi: 10.1002/pbc.24978. [Epub ahead of print]
Abstract
PLK1, a mitotic events mediating kinase, is associated with poorly prognosed neoplasia and has not been assessed for its role in childhood ALL.
5. Reduced efficacy of the Plk1 inhibitor BI 2536 on the progression of hepatocellular carcinoma due to low intratumoral drug levels. Neoplasia. 2012 May;14(5):410-9.
Abstract
BI 2536, a Plk1 inhibitor, reduced HCC cell viability, inhibited HCC xenograft progression in nude mice and diminished hepatocarcinogenesis in TGF α/c-myc bitransgenic mice. However, BI 2536 hardly affect HCC progression in the transgenic mouse HCC model due to resistance caused by low intratumoral levels of BI 2536.

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Background on BI 2536

BI 2536 is a potent, ATP-competitive, well tolerated and highly specific human polo-like kinase 1 (PLK1) inhibitor with IC value of 0.83 nM, which shows 1000-fold selectivity against other kinases [1].

BI 2536 has been demonstrated to suppress cell growth and colony formation, it has been shown to induce mitotic arrest at G2/M phase and apoptosis in human cervical adenocarcinoma cell line HeLa [2].

BI 2536 has shown to have the effect of inhibiting cell proliferation in more than 20 tumor cell lines with half maximal effective concentration (EC50) values ranging from 2–25 nM. In vivo, multiple studies in xenograft models of human carcinoma have shown the anti-tumor activity of BI 2536 when the drug was intravenously administered 1-2 times every week [1].

References:
[1] Schöffski P. Polo-like kinase (PLK) inhibitors in preclinical and early clinical development in oncology. Oncologist. 2009 Jun;14(6):559-70.
[2] Pezuk JA1, Brassesco MS, Oliveira JC, Morales AG, Montaldi AP, Sakamoto-Hojo ET, Scrideli CA, Tone LG. Antiproliferative in vitro effects of BI 2536-mediated PLK1 inhibition on cervical adenocarcinoma cells. Clin Exp Med. 2013 Feb;13(1):75-80.

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References on BI 2536

Pharmacological inhibition of Polo-like kinase 1 (PLK1) by BI-2536 decreases the viability and survival of hamartin and tuberin deficient cells via induction of apoptosis and attenuation of autophagy.[Pubmed:25565629]

Cell Cycle. 2015;14(3):399-407.

The mechanistic target of rapamycin complex 1 (mTORC1) increases translation, cell size and angiogenesis, and inhibits autophagy. mTORC1 is negatively regulated by hamartin and tuberin, the protein products of the tumor suppressors TSC1 and TSC2 that are mutated in Tuberous Sclerosis Complex (TSC) and sporadic Lymphangioleiomyomatosis (LAM). Hamartin interacts with the centrosomal and mitotic kinase polo-like kinase 1 (PLK1). Hamartin and tuberin deficient cells have abnormalities in centrosome duplication, mitotic progression, and cytokinesis, suggesting that the hamartin/tuberin heterodimer and mTORC1 signaling are involved in centrosome biology and mitosis. Here we report that PLK1 protein levels are increased in hamartin and tuberin deficient cells and LAM patient-derived specimens, and that this increase is rapamycin-sensitive. Pharmacological inhibition of PLK1 by the small-molecule inhibitor BI-2536 significantly decreased the viability and clonogenic survival of hamartin and tuberin deficient cells, which was associated with increased apoptosis. BI-2536 increased p62, LC3B-I and GFP-LC3 punctae, and inhibited HBSS-induced degradation of p62, suggesting that PLK1 inhibition attenuates autophagy. Finally, PLK1 inhibition repressed the expression and protein levels of key autophagy genes and proteins and the protein levels of Bcl(-)2 family members, suggesting that PLK1 regulates both autophagic and apoptotic responses. Taken together, our data point toward a previously unrecognized role of PLK1 on the survival of cells with mTORC1 hyperactivation, and the potential use of PLK1 inhibitors as novel therapeutics for tumors with dysregulated mTORC1 signaling, including TSC and LAM.

An open-label, phase II study of the polo-like kinase-1 (Plk-1) inhibitor, BI 2536, in patients with relapsed small cell lung cancer (SCLC).[Pubmed:28212994]

Lung Cancer. 2017 Feb;104:126-130.

OBJECTIVES: This phase II, open-label study was designed to evaluate the response rate to the polo-like kinase 1 (Plk-1) inhibitor BI 2536 in patients with sensitive-relapsed small cell lung cancer (SCLC). Secondary endpoints included progression-free survival (PFS), overall survival (OS), duration of response, and safety. MATERIALS AND METHODS: Patients were treated with the recommended phase II dose of 200mg of BI 2536 intravenously every 21days. This was a two-stage design with an early stopping rule in place if responses were not seen in at least 2 of the first 18 enrolled patients. RESULTS AND CONCLUSION: Twenty-three patients were enrolled in the study and 21 patients were evaluable for response. No responses were observed and all 23 patients have progressed. The median PFS was 1.4 months. Treatment was generally well tolerated and the most frequent adverse events were neutropenia, fatigue, nausea, vomiting, and constipation. BI 2536 is not effective in the treatment of sensitive relapsed SCLC. The criteria for expanding the trial to the second stage were not achieved, and the study was terminated for a lack of efficacy.

BRD4 Structure-Activity Relationships of Dual PLK1 Kinase/BRD4 Bromodomain Inhibitor BI-2536.[Pubmed:26191363]

ACS Med Chem Lett. 2015 May 18;6(7):764-9.

A focused library of analogues of the dual PLK1 kinase/BRD4 bromodomain inhibitor BI-2536 was prepared and then analyzed for BRD4 and PLK1 inhibitory activities. Particularly, replacement of the cyclopentyl group with a 3-bromobenzyl moiety afforded the most potent BRD4 inhibitor of the series (39j) with a K i = 8.7 nM, which was equipotent against PLK1. The superior affinity of 39j over the parental compound to BRD4 possibly derives from improved interactions with the WPF shelf. Meanwhile, substitution of the pyrimidine NH with an oxygen atom reversed the PLK1/BRD4 selectivity to convert BI-2536 into a BRD4-selective inhibitor, likely owing to the loss of a critical hydrogen bond in PLK1. We believe further fine-tuning will furnish a BRD4 "magic bullet" or an even more potent PLK1/BRD4 dual inhibitor toward the expansion and improved efficacy of the chemotherapy arsenal.

PLK1 expression and BI 2536 effects in childhood acute lymphoblastic leukemia.[Pubmed:24519995]

Pediatr Blood Cancer. 2014 Jul;61(7):1227-31.

BACKGROUND: Polo-like kinase 1 (PLK1) is a conserved kinase that mediates various mitotic events. Compelling data have repeatedly demonstrated its upregulation in different neoplasia, being frequently associated with poor prognosis. However, in childhood acute lymphoblastic leukemia (ALL), no studies have yet been conducted. PROCEDURE: PLK1 expression and association with biological features were evaluated in 65 consecutively diagnosed childhood ALL samples by quantitative real-time PCR. Moreover, the effects of a specific PLK1 inhibitor, BI 2536, was tested against a panel of nine ALL cell lines at nanomolar concentrations (10, 50, 100 nM). RESULTS: The mRNA expression of PLK1 showed great variability in pediatric ALL, but no difference was evidenced compared to normal bone marrow. Additionally, no association was found between PLK1 mRNA expression with any clinical or biological features. Alternatively, high mRNA expression of PLK1 was present in ALL cell lines. In vitro treatment with BI 2536 strongly diminished growth, while presenting significant reduction in colony formation capacity and increased apoptosis rates. Moreover, strong G2/M arrest was detected suggesting important impaired proliferation after treatment. CONCLUSIONS: PLK1 mRNA expression level is not associated with prognosis in childhood ALL; however, considering the great variability observed in the sample and the in vitro experiments presented herein, BI 2536 treatment might serve as a promising therapeutic to enhance the efficacy of conventional treatment modalities in some childhood ALL cases.

Description

BI 2536 is a dual PLK1 and BRD4 inhibitor with IC50s of 0.83 and 25 nM, respectively. BI-2536 suppresses IFNB (encoding IFN-β) gene transcription.

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