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.3?BI 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.
References
1) Steegmaier?et al.?(2007),?BI 2536, a Potent and Selective Inhibitor of Polo-like Kinase 1, Inhibits Tumor Growth In Vivo; Curr. Biol.,?17?316
2) Davis?et al.?(2011),?Comprehensive analysis of kinase inhibitor selectivity; Nat. Biotechnol.,?29?1046
3) Ciceri?et al.?(2014),?Dual kinase-bromodomain inhibitors for rationally designed polypharmacology; Nat. Chem. Biol.,?10?305
4) Xiao?et al.?(2016),?Polo-like Kinase-1 Regulates Myc Stabilization and Activates a Feedforward Circuit Promoting Tumor Cell Survival; Mol. Cell,?64?493
[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
