In 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.

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.

MEDICINE tomorrow

The Campaign for Yale School of Medicine

"Finding a New Chink in Cancer's Armor" documents the 10-year effort of Joseph Schlessinger, PH.D., and his colleagues to determine the molecular structure of a receptor involved in many cancers in order to develop better drugs. Structural biology, cancer, and drug development are top priorities of The Campaign for Yale School of Medicine. The Campaign will provide resources to:

  • recruit and honor superb faculty by endowing professorships and Yale scholars;
  • pursue research to advance medicine;
  • secure cutting-edge technology for research;
  • move research from bench to bedside;
  • invest in outstanding patient care;
  • support and nurture medical and graduate students with funds for scholarships, fellowships, student research and educational innovation;
  • meet the pressing demand for space by building a new cancer hospital and additional research laboratories.

Why is this campaign important? Because at no point in history has medical research made advances at the rate and pace of the last 10 year, and this progress will pale by comparison to what Yale School of Medicine is poised to accomplish in the years ahead.

For more information about gift opportunities, visit Yale Tomorrow Medicine or contact Jancy Houck, Associate Vice President for Development and Director of Medical Development at (203) 436-8560.