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| Product Name: | BI 2536 | | Synonyms: | BI-2536, BoehringerPLK-1 inhibitor;4-[[(7R)-8-Cyclopentyl-7-ethyl-5,6,7,8-tetrahydro-5-methyl-6-oxo-2-pteridinyl]amino]-3-methoxy-N-(1-methyl-4-piperidinyl)benzamide;BI 2536;Benzamide, 4-[[(7R)-8-cyclopentyl-7-ethyl-5,6,7,8-tetrahydro-5-methyl-6-oxo-2-pteridinyl]amino]-3-methoxy-N-(1-methyl-4-piperidinyl)-;Boehringer PLK-1 inhibitor;BI-2536(R-);BI2536/BI-2536;(R)-4-((8-cyclopentyl-7-ethyl-5-Methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)aMino)-3-Methoxy-N-(1-Methylpiperidin-4-yl)benzaMide | | CAS: | 755038-02-9 | | MF: | C28H39N7O3 | | MW: | 521.65 | | EINECS: | 1308068-626-2 | | Product Categories: | Inhibitors;API | | Mol File: | 755038-02-9.mol |  |
| | BI 2536 Chemical Properties |
| density | 1.28 | | storage temp. | Keep in dark place,Sealed in dry,Store in freezer, under -20°C | | solubility | Soluble in DMSO (up to 20 mg/ml) or in Ethanol (up to 25 mg/ml) | | form | Yellow powder. | | pka | 14.09±0.20(Predicted) | | color | Off-white | | Stability: | Stable for 1 year from date of purchase as supplied. Solutions in DMSO or ethanol may be stored at -20°C for up to 3 months. | | InChIKey | XQVVPGYIWAGRNI-JOCHJYFZSA-N | | SMILES | C(NC1CCN(C)CC1)(=O)C1=CC=C(NC2=NC=C3C(=N2)N(C2CCCC2)[C@H](CC)C(=O)N3C)C(OC)=C1 |
| | BI 2536 Usage And Synthesis |
| Description | BI 2536 (755038-02-9) was originally reported as a potent (IC50’s Plk1 = 0.83nM, Plk2 = 3.5nM and Plk3 = 9.0nM) and selective Polo-like kinase inhibitor that caused mitotic arrest and apoptosis induction in various human cancer cell lines. It was later found to be a potent inhibitor (IC50 = 100nM) of BET family member BRD4 and able to potently suppress c-Myc expression in MM.1S multiple myeloma cells.3BI 2536 destabilizes N-Myc by inhibiting the deactivation of the ubiquitin E3 ligase Fbw7 by Plk1[1-4]. | | Uses | BI 2536 is a PLK1 inhibitor, inducing apoptosis together with micro-tubule-destabilizing drugs in preclinical rhabdomyosarcoma models. Anti-cancer and potent PLK1 inhibitor. | | Biological Activity |
BI 2536, an ATP-competitive PLK1 kinase inhibitor, has been shown to inhibit PLK1 enzyme activity at nanomolar concentrations. Studies showed that BI 2536 treatment resulted in cell cycle progression disorder, mitotic catastrophe, growth inhibition and apoptosis in a broad range of cancer cells. Given its potent anti-proliferation activity in various cancer cells and xenograft models, the effect of this compound has been evaluated in clinical studies in several adult cancers.[5].
| | in vitro |
Exceeding a 100-fold concentration range starting at 10 nM, BI 2536 causes HeLa cells to accumulate with a 4N DNA content, indicative of a cell-cycle block in either the G2 phase or mitosis. In addition to HeLa cells, BI 2536 potently inhibits the proliferation of a panel of 32 human cancer cell lines, representing diverse organ derivations (including carcinomas of the breast, colon, lung, pancreas, and prostate, melanomas, and hematopoietic cancers) and varied patterns of tumour suppressor or oncogene mutations (including RB1, TP53, PTEN, andKRAS status). The half-maximal effective concentration (EC50) values in this cell panel ranged from 2-25 nM, whereas a concentration of 100 nM of BI 2536 is typically sufficient for inducing a complete mitotic arrest. The proliferation of exponentially growing hTERT-RPE1, human umbilical vein endothelial cells (HUVECs), and normal rat kidney (NRK) cells are blocked at EC50values ranging from 12-31 nM, indicating a comparable sensitivity of cycling nontransformed cells to BI 2536.
| | in vivo |
BI 2536 (40-50 mg/kg, i.v.) blocks the growth of human cancer xenografts in immunodeficient nu/nu mice. Consecutive cycles of 40-50 mg/kg BI 2536 given i.v. Once or twice per week are found to be highly efficacious in diverse xenograft models, such as the HCT 116 colon cancer with complete tumour suppression with the twice per week schedule (treated versus the control (T/C) value 0.3%) and a T/C value of 16% with once per week treatment; both schedules are well-tolerated, as judged by clinical signs and absence of significant body-weight changes.
| | target | Plk1 | | Background | BI 2536 is a small molecule inhibitor of mammalian polo-like kinases with a strong selectivity for PLK1. PLK1 is important in regulating mitosis and is often overexpressed in cancers, contributing to excessive cell proliferation and loss of key checkpoint functions. Research indicates that BI 2536 causes mitotic arrest and apoptosis in 32 unique human cancer cell lines and inhibits the growth of human tumor xenografts in nude mice, with little to no effect on healthy cells. This along with the fact that BI 2536 exhibits high permeability through the blood-brain barrier, makes it an important therapeutic tool. BI 2536 inhibits BRD4 and BRD4-dependent c-Myc expression in MM.1S multiple myeloma cells. Recently, BRD4 inhibition has shown anti-viral activity and increased host resistance to several DNA and RNA viruses, making BRD4 disruptors important compounds to study in relation to viral diseases. | | References | 1) Steegmaieret al.(2007),BI 2536, a Potent and Selective Inhibitor of Polo-like Kinase 1, Inhibits Tumor Growth In Vivo; Curr. Biol.,17316
2) Daviset al.(2011),Comprehensive analysis of kinase inhibitor selectivity; Nat. Biotechnol.,291046
3) Ciceriet al.(2014),Dual kinase-bromodomain inhibitors for rationally designed polypharmacology; Nat. Chem. Biol.,10305
4) Xiaoet al.(2016),Polo-like Kinase-1 Regulates Myc Stabilization and Activates a Feedforward Circuit Promoting Tumor Cell Survival; Mol. Cell,64493
[5] Li, Zhiheng et al. “The dual role of BI 2536, a small-molecule inhibitor that targets PLK1, in induction of apoptosis and attenuation of autophagy in neuroblastoma cells.” Journal of Cancer vol. 11,11 3274-3287. 5 Mar. 2020, doi:10.7150/jca.33110 |
| | BI 2536 Preparation Products And Raw materials |
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