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September 12, 2011
From the RSC/SCI Symposium: A Med-Chem Anomaly
Well, actually, this might not be an anomaly. Medicinal chemists will have heard of the "magic methyl" effect, where small changes can make a big difference in affinity for a drug candidate. This morning I heard an interesting talk by Phil Sanderson of Merck on allosteric Akt inhibitors for cancer. I won't go into all the kinase-ness, although it was definitely worth hearing about. What caught my eye was something he mentioned at the end of the talk. The first compound below was an early screening hit in their work, something that had been in Merck's files since the early 1970s. After a huge amount of work over many years, which you can follow though the literature if you like with a search for "allosteric" and "Akt", they found that four-membered rings were very useful in the structures. Going back to the original structure and adding that same modification to it improved its potency by roughly 100-fold.
One methylene group! You wonder what might have happened if they'd done that early in the project, but as Sanderson correctly noted, no one would have done that (it's synthetically tricky; no one would have put in the time). And they don't have any structural information that seems to explain this effect, he says. So if you're looking for an illustration of what makes medicinal chemistry the wild ride it is, you've got an excellent one here.
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