“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 typically binds adenosine triphosphate (ATP). Several second-generation mTOR inhibitors are currently in clinical trials. Unfortunately, tumor cells have proven talented at developing mutations that make both first- and second-generation mTOR inhibitors ineffective. Shokat, Rosen, and coworkers determined that the two binding sites in mTOR are 15 Å away from one another. So they took rapamycin and a second-generation inhibitor called MLN0128, which binds mTOR’s ATP site, and combined them with a polyethylene glycol-based linker that spans that gap between the two sites.
by Stu Borman |
May 19, 2016