Researchers Get Atomic View of FPT Inhibitors in Action

Many pharmaceutical companies are engaged in the race to develop farnesyl protein transferase (FPT) inhibitors, a new class of cancer-fighting drugs that incapacitate an enzyme recently found to activate many types of cancer. Now, researchers at Schering-Plough Research Institute (Kenilworth, NJ) report what they say is the first atomic view showing how FPT inhibitors work. The team's findings, which will appear in the May 1 edition of the Journal of Medicinal Chemistry, may point the way to faster, better refinement of the drugs.

FPT puts the finishing touches on a protein made under the direction of a mutated gene called ras (short for "rat sarcoma," because the gene's cancer connection was originally discovered in rats). Normally, a completed Ras protein attaches to cell membranes, where it signals cells to grow when appropriate. The mutation, which causes a single kink in the Ras protein structure, leaves it stuck in the "on" position. Out of control growth then ensues, causing cancer.

Since the gene's discovery in the early 1990s, the ras mutation has been linked to 90% of pancreatic cancers, 50% of colon cancers, and 30% of lung cancers. Researchers hope that by attacking FPT—instead of cell replication machinery directly—they can more specifically inhibit cancer and lessen collateral damage to normal cells.

A wave of FPT inhibitors has recently surged into clinical trials. While scientists previously had ideas about how FPT inhibitors fouled up the enzyme, the Schering-Plough study used crystallographic analysis to actually view the interaction. According to co-author and Schering-Plough Research Institute chemist Patricia Weber, the findings validate that idea that the compounds do bind to the active site of the farnesyl protein transferase. The study focuses on Schering-Plough's clinical candidate, SCH 66336, which is in Phase II efficacy trials directed against a variety of solid tumors.

While the company maintains that no trial results are available yet, Weber says the new images "allow a detailed understanding of how and why these inhibitors work—and it is our expectation that, in the future, the combination of synthetic chemistry and x-ray crystallography will lead to the development of more potent, second generation FPT inhibitors."

For more information: Patricia Weber, Schering-Plough Research Institute, 2015 Galloping Hill Rd., Kenilworth, NJ 07033. Tel: 908-298-5557.