Today let’s go on talking about PLK inhibitor. Yesterday I mentioned that PLK1 plays a key role in the mitotic entry, centrosome duplication, bipolar mitotic spindle formation, transition from metaphase to anaphase, cytokinesis and maintenance of genomic stability. Some PLK inhibitors were developed to using in cancer therapy. BI 2536 and GSK461364A are under clinical trials have the study results revealed that they both have potency in cancer treatment. Italo Beria et al. found that 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline is a wonderful scaffold to obtain potent and selective PLK1 inhibitors. They did some research on this scaffold to develop the potency, selectivity and oral bioavailability of this compound prospect to find new PLK1 inhibitors. Their study results were published on Bioorganic & Medicinal Chemistry Letters (2011). We have already known that PLK is an important element that regulates cell cycle progression, particularly mitosis. Four subtype PLK families have been identified so for: PLK1, PLK2, PLK3 and PLK4. In these subtypes, PLK1 is the most investigated member and has most tightly relationship with cancer development. PLK1 is expressed primarily in dividing cells and involve in activation of CDC25c phosphatase, regulation of microtubule nucleation, centrosome maturation, kinetochore assembly and regulation of cytokinesis. Eight kinds of PLK1 inhibitors have been introduced in their article: BI 2536, GSK461364A, SBE13, LFM-A3, HMN-214, ON 01919.Na, Poloxin and Purpurogallin. BI 2536 and GSK461364 are ATP-competitive inhibitors. But their mechanism is still unknown. BI 2536 is a potent and selective inhibitor for PLK, it is mainly targeting PLK1. This compound now is under phase II clinical trials. More information about this compound I will introduce in later posts. GSK461364A is another ATP-competitive PLK1 inhibitor, which are under phase I clinical trials. HMN-214 is an oral prodrug of HMN-176, acts on the PLK1 pathway. Its exact mechanism of action and specificity is still unknown. ON 01919.Na is under phase I clinical trials which is preformed to establish DLTs and PK/PD parameters. SBE13 is a PLK1 selective inhibitor with 0.2nM inhibitory activity against PLK1, PLK2 and PLK3 is not sensitive to this compound. LFM-A13 is testing for PLX1 inhibition in vitro with an IC50 value of 10M. It also inhibits PLK3 activity with IC50 value of 61M, but it doesn’t affect PLK2 activity. Poloxin, a synthetic derivative of the natural product thymoquinone 8, had an IC50 of 5mM for PLK1. Thymoquinone is a less specific inhibitor, which inhibited PLK1 and some other kinases. The mother compound is shown as above, the researchers did some structural modification on 5’ and 1 position, and obtained a series of derivates. Among these derivates, they found 7g (NMS-P937) is the most potency compound, and they did some PK/PD and in vivo activity studies using this compound. The i.v. PK results of 7g shown that AUC is about 8.57M h, CL is about 2.36L/h/kg. t1/2 is about 0.89h. the p.o. PK data of 7g shown that AUC is about 2.04M h, Cmax is about 0.64M, t1/2 is about 1.60. The in vivo activity study was performed in HCT116 tumor cell inoculation nude mice. The treatment method is 1-3 bid*2 weekly cycles. The dose is 45mg/kg. The data shown that %TGImax is about 83 day, the %BWLmax is about 16 day. Related Posts: PLK Inhibitor BI 2536 in Drug Resistance PLK Inhibitor: Potent Way to Treating Neuroblastoma Review of PLK1 Inhibitors
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