This entry was posted on June 18, 2009 at 8:12 am and is filed under Aurora, Takeda.
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I thought it still wasn’t clear which Aurora would be the better target. Inhibtion of each leads to different phenotypes in vitro (4N+ DNA for B, earlier block in M for A), but as far as a therapeutic window in vivo, I thought each have been shown to have efficacy, but only at doses very close to the doses that cause severe toxicity. I understand the Vertex/Merck AurB compound failed for non-mechanism reasons, so I don’t know when the first POC study will be complete for either one of these targets. Am I wrong? Can you dose AurB inhibitors well above the efficacious dose without tox?
Most of the “pan” Aurora inhibitors (like VX-680, which is actually somewhat more potent for AurA than B) induce phenotypes similar to Aurora B inhibition “only”. However, data using antisense oligos on pancreatic cancer cells have shown AuroA inhibitions is better target that AuroB. OTOH, RNAi studies using colon cancer cell lines showed that they were very sensitive to AuroB inhibition. And then there was a study showing inactivn of AuroB bypassing AuroA. AstraZeneca was touting their highly B selective compounds in few compounds. And Millenium’s AK inhibitor is highly A selective. These compounds and many others are still in trials, AFAIK. So I think the jury is still not out yet.