Drug Design Strategy May Fight Cancer More Effectively with Fewer Side Effects

Sinai Medical Center (New York, NY, USA). Instead of looking for find magic bullets--chemicals that specifically attack one gene or protein involved in one specific part of a disease process--the new approach is searching for “magic shotguns” by sifting through the known field of chemicals to find the few special molecules that broadly disrupt the whole diseases process.

“We’ve always been looking for magic bullets,” said Kevan Shokat, PhD, chair of the department of cellular and molecular pharmacology at UCSF. “This is a magic shotgun--it doesn’t inhibit one target but a set of targets--and that gives us a much, much better ability to stop the cancer without causing as many side effects.”

Described in the June 7, 2012, issue of the journal Nature, the magic shotgun approach has already provided two potential drugs, called AD80 and AD81, which in fruit flies were more effective and less toxic than the drug vandetanib, approved by the US Food and Drug Administration (FDA) last year for the treatment of a certain type of thyroid cancer.

Drug design essentially entails disruption: in any disorder, there are many molecular interactions and other mechanisms that take place within specific tissues, and in the widest sense, most drugs are simply chemicals that interfere with the proteins and genes involved in those processes. The better a drug disrupts key parts of a disease process, the more effective it is.

The toxicity of a drug, however, refers to how it also disrupts other parts of the body’s system. Drugs always fall short of perfection in this sense, and all pharmaceuticals have some level of toxicity due to unwanted interactions the drugs have with other molecules in the body.

Scientists utilize the therapeutic index (the ratio of effective dose to toxic dose) as a way of defining how severe the side effects of a given drug would be. Many of the safest drugs on the market have therapeutic indexes that are 20 or higher--meaning that a person would have to take 20 times the prescribed dose to suffer severe side effects.

Many cancer drugs, on the other hand, have a therapeutic index of 1. In other words, the amount of the drug you need to take to treat the cancer is the exact amount that causes severe side effects. The difficulty, according to Dr. Shokat, is that cancer drug targets are so similar to normal human proteins that the drugs have widespread effects felt far outside the tumor.

While suffering the side effects of drugs is a reality that many people with cancer face, finding ways of minimizing this toxicity is a big aim pharmaceutical companies would like to resolve. Dr. Shokat and his colleagues believe the shotgun approach is one way to achieve this. The view that the best drugs are the most selective could be mistaken, Dr. Shokat noted, and for cancer, a magic shotgun may be more effective than a magic bullet.

Studying fruit flies, the investigators found a way to screen compounds to find the few that best disrupt an entire network of interacting genes and proteins. Instead of assessing a compound according to how well it suppresses a specific target, they deemed as best the compounds that inhibited not only that specific target but disrupted other areas of the network while not interacting with other genes and proteins that would cause toxic side effects.

Related Links:
University of California, San Francisco
Mt. Sinai Medical Center