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July 25, 2013
Kevan Shokat At The Challenges in Chemical Biology Conference
Kevan Shokat is now talking about his lab's work on using Drosophila models for kinase inhibitor discovery in oncology. I always like hearing about this sort of thing; very small living models have a lot of appeal for drug discovery.
You'd think that screening in fruit flies would be problematic for understanding human efficacy, but if you pick your targets carefully, you can get it to work. In Shokat's case, he's looking at a kinase called Ret, which is a target in thyroid cancer and is quite highly conserved across species. They set up a screen where active compounds would rescue a lethal phenotype (which gives you a nice high signal-to-noise), and screened about a thousand likely kinase inhibitor molecules.
Here's the paper that discusses much of what Shokat's group found. It turned out that Ret kinase inhibition alone was not the answer - closely related compounds with very similar Ret activity had totally different phenotypes in the flies. The key was realizing that some of them were hitting and missing other kinases in the pathways (specifically Raf and TOR) that could cancel out (or enhance) the effects. This was a very nice job of direct discovery of the right sort of kinase fingerprint needed for a desired effect. We need more tiny critters for screens like these.
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