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Xenical (orlistat) being modified to make it a bc treatment
I have previously posted on how xenical is synergistic with herceptin (makes it a more effective drug ) against her2+ breast cancer. Unfortunately it is not absorbed when take orally (hence its effect/side
effects) in causing weightloss/diarrhea. It is now being modified to take advantage of its targeted action and increase its bioavailability (how much of a given dose is actually available to the body to work.
Luckily xenical itself is made by the same company that owns the majority of Genentech, making a trial of combined therapy more likely. Don't know if that company, Roche, will pick up on this research, since it is Xenical, rather than these modifications which is their product. Wishing them speedy and great results!
Discovery about obesity drug helping scientists develop new cancer treatments [Eureka News Service]
WINSTON-SALEM, N.C. - Based on their surprising discovery that an obesity drug can kill cancer cells, scientists at Wake Forest University School of Medicine have made a new finding about the drug's effects and are working to design more potent cancer treatments.
Published online today in Nature Structural and Molecular Biology, the study is the first to report how the drug orlistat (Xenical® or Alli®) binds and interacts with a protein found in tumor cells. The drug blocks the protein's function and causes cell death.
The project started five years ago when Steven Kridel, Ph.D., an assistant professor in the Department of Cancer Biology, analyzed prostate cancer cells to see which enzymes were expressed at high levels. His hope was that treatments to inhibit those enzymes could also stop tumor growth.
"We found that a protein known as fatty acid synthase is expressed at high levels in prostate tumor cells, and is fairly absent in normal cells," said Kridel.
Other research has shown that the protein is found in many tumor cells including breast, colon, ovarian, liver, lung and brain.
"High levels of fatty acid synthase correlate with a poor prognosis so it is a great treatment target," said Kridel. "This makes an exciting treatment target because theoretically you don't have to worry about harming nearby healthy tissue."
Unfortunately, orlistat itself cannot be used as a cancer treatment because, while it can kill cancer cells in the laboratory, in humans it is designed to act only in the digestive tract.
"Understanding this drug-protein interaction is essential for designing new drugs," said W. Todd Lowther, Ph.D., an assistant professor in the Department of Biochemistry. "We've used a technique known as X-ray crystallography and now have a three-dimensional snapshot of the drug interacting with the protein."
"Our goal is to develop an orlistat-like drug that can get into the bloodstream and go to the site of a tumor," said Lowther.
Once they developed the three-dimensional map of the interaction, Lowther and Kridel began screening hundreds of thousands of compounds to identify those that interact with cancer cells in the same way as orlistat. They have narrowed the list of possibilities down to a dozen and will now work to optimize the compounds in hopes of creating potent cancer treatments. The drugs will first be tested in animals and then in human cancer patients.
Fatty acid synthase is also found in fat cells, which suggests that if the scientists are successful in developing an anti-cancer drug, it could also be an effective obesity drug.
"You might have the same drug for treating a cancer patient as an obese patient," said Lowther.
ABSTRACT: Crystal structure of the thioesterase domain of human fatty acid synthase inhibited by Orlistat [Nature Structural and Molecular Biology]
Human fatty acid synthase (FAS) is uniquely expressed at high levels in many tumor types. Pharmacological inhibition of FAS therefore represents an important therapeutic opportunity. The drug Orlistat, which has been approved by the US Food and Drug Administration, inhibits FAS, induces tumor cell-specific apoptosis and inhibits the growth of prostate tumor xenografts. We determined the 2.3-?-resolution crystal structure of the thioesterase domain of FAS inhibited by Orlistat. Orlistat was captured in the active sites of two thioesterase molecules as a stable acyl-enzyme intermediate and as the hydrolyzed product. The details of these interactions reveal the molecular basis for inhibition and suggest a mechanism for acyl-chain length discrimination during the FAS catalytic cycle. Our findings provide a foundation for the development of new cancer drugs that target FAS.
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