Kinase Chemistry – Just a year and a half behind the times.


Posted by kinasepro on April 2, 2009

Onconova’s IV Ph2 PLK1’inhibitor’


…a new chemical entity that arrests cancer cells in G2/M by modulating mitotic regulatory pathways including polo-like kinase 1 (Plk1).” via WO/2008/088803

8 Responses to “ON-01910”

  1. AliG said

    I love how you put inhibitor in quotes. It’s not really clear what this compound does, but it certainly doesn’t inhibit PLK1.

  2. kinasepro said

    It certainly doesn’t look like a kinase domain / ATP mimetic, but the vinyl sulphone likely alkyates a cysteine residue somewhere inactivating the pathway… where? I dunno.

  3. ATP->ADP said

    ON-01910 and BI-2536 are both inhibitors of PLK-1. They don’t even look like distant cousins! Any idea of the binding mode?

  4. Samsleshana said

    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).

  5. AliG said

    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.

  6. Samsleshana said

    Now there is no question about the activity of this compound.

  7. viledonkey said

    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….

  8. AliG said

    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.

Leave a Reply

Fill in your details below or click an icon to log in: Logo

You are commenting using your account. Log Out /  Change )

Google photo

You are commenting using your Google account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s

%d bloggers like this: