Science Concentrates NH2 O
ONCOLOGY
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Combination inhibitor fights drugresistant cancer
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Shokat has patented the new drug design for development by Kura Oncology, a company he helped found. “This is a very important paper with huge potential for cancer therapy,” says Nahum Sonenberg, an mTOR and cancer specialist at McGill University. mTOR controls a cell-signaling pathway that is commonly activated in many human cancers. Researchers developed everolimus and temsirolimus to inhibit that pathway. The drugs, analogs of the bacterial natural product rapamycin, target a rapamycin-binding site in mTOR. A more recently developed “second generation” of mTOR inhibitors work by hitting another mTOR site, where the enzyme binds adenosine triphosphate (ATP). Several second-generation mTOR inhibitors are currently in clinical trials. But tumor cells are talented at developing mutations that make first- and second-generation mTOR inhibitors ineffective. Shokat, Rosen, and coworkers took
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Strategy could help patients whose malignancies sidestep drugs that hit key cancer target mTOR Cancer can be a wily foe. A recent article in New York Times Magazine tells the story of a woman whose thyroid cancer developed resistance to the chemotherapy drugs everolimus and temsirolimus. The drugs are supposed to work by inhibiting an enzyme, mTOR, that helps cancer cells grow. But her cancer mutated, rendering the drugs ineffective. The May 15 article “covers the type of cancer patient and emerging resistance that stimulated our new work on mTOR inhibitors,” says Kevan Shokat of the University of California, San Francisco. Shokat, Neal Rosen of Memorial Sloan Kettering Cancer Center, and coworkers report a drug candidate that’s more potent than approved mTOR inhibitors and less likely to be defeated by drug resistance. They accomplished the feat by combining two types of mTOR inhibitors, which hit separate target sites on the enzyme, into a bivalent agent that hits both simultaneously (Nature 2016, DOI: 10.1038/nature17963).
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RapaLink-1: Linker
rapamycin and a is black, rapamycin second-generation is blue, and inhibitor called MLN0128 is red. MLN0128, which binds mTOR’s ATP site, and combined them with a polyethylene glycol-based linker that spans the 15-Å gap between the two sites. This third-generation agent, dubbed RapaLink-1, binds both sites simultaneously and potently inhibits the growth of nonresistant and drug-resistant cancers in tumor cell cultures and in mice. Kinase inhibitor expert Nathanael Gray of Dana-Farber Cancer Institute says he wouldn’t have predicted that such a large molecule would be effective. But he says that two characteristics of RapaLink-1—its bivalency and its tendency to concentrate in red blood cells that deliver it to cancers— likely account for its high potency. He notes that cancers are less likely to find a way to sidestep its activity because they would need to mutate twice instead of just once to mount resistance.—STU BORMAN
FLUORINATION
Mechanistic insights on deoxyfluorination In 2011, when Tobias Ritter reported a reagent—now known as PhenoFluor— that could swap the hydroxyl group on a phenol for a fluoride, he was cautiously optimistic that the work might someday be used to make radiotracers with 18 F. After all, the deoxyfluorination reaction, which proceeds via nuclear aromatic substitution, opened up more options. It worked on phenols that were electron-rich, whereas other such reactions worked only on electron-poor arenes.
An example of Ritter and coworkers’ deoxyfluorination reaction with 18F.
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C&EN | CEN.ACS.ORG | MAY 23, 2016
But the radiolabeling version of the reaction proved elusive. So Ritter and graduate student Constanze N. Neumann, both at Harvard University at the time, decided to dig into the reaction mechanism. They discovered that the de-
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oxyfluorination takes place in a concerted fashion: The fluoride goes onto the aromatic ring at the same time the oxygen leaves the ring in the form of a urea compound (Nature 2016, DOI: 10.1038/nature17667). With the knowledge they gleaned about the mechanism, Ritter and Neumann teamed up with Jacob M. Hooker, of Massachusetts General Hospital, to tweak PhenoFluor so that it could work 18F with 18F. “This new reaction is much more robust, tolerates air and water, and, most importantly, is really easy to perform,” says Ritter, who recently CN moved to the Max Planck Institute for Coal Research.—BETHANY HALFORD
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