Inside this issueCover storiesPassing the torchAcquisition of Bayer site will accelerate biomedical researchInternational effort rewrites the book on the human genomePartnershipsFoundation supports Yale research “of practical benefit”Grants & contractsPeopleLifelines: Lawrence CohenYale scientist is new president of Wellesley CollegeTop heart surgeon is named Glenn ProfessorDiabetes experts win top scientific honorsObstetrics/gynecology chair is honored as leader and writerOut & aboutAwards & honorsScienceFinding a new chink in cancer's armorResearch center aims to make rickets historyBrewing a new treatment for kidney diseaseAdvances: Putting a squeeze on Lyme disease | These mice like to spend time chilling | Hearing voices: A brain out of sync? | Stem cells show promise in Parkinson's  
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Finding a new chink in cancer’s armorClose-up view of protein offers hope for new, highly targeted cancer drugsIn the July 27 issue of Cell, a research team led by Joseph Schlessinger, Ph.D., William H. Prusoff Professor and chair of pharmacology, reports solving the atomic-level structures for the active and inactive forms of a protein that has been implicated in several types of cancer. The results highlight previously unidentified changes in the protein’s structure that seem to be crucial for its activation. Drugs designed to block these changes could represent a novel class of therapies with the potential to work against a broad range of cancers.
“It gives us totally new avenues for developing drugs for a large group of target proteins that are responsible for several cancers,” says Schlessinger. The study focused on one of 59 receptor tyrosine kinases (RTKs), a set of related proteins that normally become active only under particular circumstances to help cells proliferate, differentiate and survive. Certain mutations in RTKs can turn the proteins on inappropriately, causing aberrant cell proliferation that may ultimately lead to cancer. Blocking the activities of RTKs has become a major strategy in anticancer drug design, so knowing the structures of the proteins can tell researchers which parts are important for turning the proteins on and would therefore make good drug targets. In general, RTKs have three major parts: an intracellular component, a portion embedded in the cell’s membrane, and an extracellular domain that extends to the outside of the cell. Normally, each RTK binds specifically to an external signaling molecule called a ligand via its extracellular domain. Binding permits two molecules of the RTK to come together, forming a paired structure known as a dimer. Once dimerized, pockets within the intracellular portions of the RTKs bind to adenosine triphosphate, or ATP—an energy-storing molecule found inside cells—and use it to modify themselves in such a way that they are active and able to modify and assemble other factors inside the cell to promote cell growth. Two recently developed and highly successful cancer-fighting drugs, Gleevec and Sutent, work by preventing the intracellular regions of some RTKs from binding ATP. Gleevec is effective against particular stomach cancers and leukemias; Sutent also works against specific stomach cancers and fights some kidney cancers. “As we speak,” says Schlessinger, “hundreds of people are being saved by these two drugs.” But Schlessinger, who helped discover Sutent, says there’s still an urgent need for new drugs. Many cancers don’t respond to Gleevec or Sutent, and those that do typically develop resistance to the drugs within a few years. With that in mind, Schlessinger has spent the last 10 years putting together a detailed atomic-level view of the extracellular domain of an RTK called Kit. All that effort has yielded a picture of the protein at atomic resolution—about a million times smaller than the thickness of a sheet of paper.
The results suggest that after binding to their ligands and forming dimers, Kit molecules change their shape such that certain portions of the extracellular domain in one Kit molecule move close enough to interact with their counterparts on the other Kit molecule in the dimer. These interacting regions represent completely new targets for cancer drugs. And since Kit is part of a family of RTKs with similar extracellular domains, the targets represented by this study probably exist in more than a half dozen other RTKs that have been implicated in various cancers. “It’s a mechanism that is likely to be universal to quite a few of these RTKs,” Schlessinger predicts. Because the targets are in the extracellular portion of the protein, scientists won’t have to worry about getting the drugs inside cells, a major challenge in drug design. And because the interactions involve relatively small portions of the extracellular domain, researchers may be able to design more effective drugs, says Mark A. Lemmon, Ph.D., of the University of Pennsylvania School of Medicine. Lemmon, who wrote a commentary accompanying Schlessinger’s report in Cell, explains that previous drug design efforts targeting the extracellular domains of Kit and Kit-related RTKs have sought to block dimerization, which involves many interactions over large portions of the protein. But it takes a big molecule—an antibody, for example—to disrupt enough of these interactions to have an impact on dimerization, and that’s not ideal. “They’re really sledgehammer drugs, and they’re not particularly good,” says Lemmon. “These are the first kinds of interactions in the extracellular domains for which you could devise small molecule inhibitors,” and that could lead to much better drugs in the long run. Most importantly, drugs aimed at these new targets might be effective against Gleevec- and Sutent-resistant cancers, offering hope to many cancer patients who are trying to stay one step ahead of the enemy. 
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