“…a new chemical entity that arrests cancer cellsin G2/M by modulating mitotic regulatory pathways includingpolo-like kinase 1 (Plk1).” via WO/2008/088803
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As we all know, there are other alternative ways to inhibit a protein kinase function other than binding at ATP pocket. This molecule may be binding at allosteric pocket/Polo-box domains of Polo-like kinase (PLK).
This compound does not inhibit the kinase function of PLK1. It alkylates tons of different proteins. That is why the authors only claim it: “arrests cancer cells in G2/M by modulating mitotic regulatory pathways including polo-like kinase 1 (Plk1)” and not that it actually inhibits PLK1. Hell, any compound that stops a cell in G2/M will “modulate” PLK1 pathway because PLK1 is cell cycle dependent.
Not convinced by these compounds. It’s a glycine analogue of ON012380, which is reported to be a non-ATP competitive inhibitor of Bcr-Abl – it has an alanine side-chain. However, ON012380 is reported to have no activity vs. PLK! Can’t believe a methyl group can make such a dramatic change in activity….
It’s interesting that Onconova’s website does not claim this as a Plk inhibitor. From there: “Mechanism of Action: ON 01910.Na is a potent and selective mitotic inhibitor, with a differential effect on cell cycle progression in tumor cells vs. normal cells. Its primary action on tumor cells is to inhibit the cell cycle progression at the G2-M stages. Chromosomes disperse in the cytoplasm and apoptosis follows. The detailed molecular mechanism of action is currently under study. Normal cells, however, are reversibly arrested at G1 and G2, without apoptosis.”
The phenotype they describe (chromosomes dispersed in the cytoplasm) is not the phenotype seen with other Plk small molecule inhibitors, antisense or siRNA.
Additionally from their website: “Tumor cell death is caused by apoptosis induced by caspase activation, independent of p53 status or bcl status.”
There have been numerous reports that mutant TP53 causes sensitivity to Plk1 inhibition. Interesting that their “Plk inhibitor” behaves so different from the other reported Plk inhibitors.