A new approach to drug design, pioneered by a
group of researchers at the University of California, San Francisco (UCSF) and
Mt. Sinai, New York, promises to help identify future drugs to fight cancer and
other diseases that will be more effective and have fewer side effects.
Rather
than seeking to find magic bullets—chemicals that specifically attack one gene
or protein involved in one particular part of a disease process—the new
approach looks to find "magic shotguns" by sifting through the known
universe 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, a Howard
Hughes Medical Institute Investigator and the 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 yielded two potential drugs, called AD80 and AD81, which
in fruit flies were more effective and less toxic than the drug vandetanib,
which was approved by the U.S. Food & Drug Administration last year for the
treatment of a certain type of thyroid cancer.
Expanding
the Targets to Lower a Drug's Toxicity
Drug
design is basically all about disruption. In any disease, there are numerous
molecular interactions and other processes that take place within specific
tissues, and in the broadest 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, on the other hand, 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
use something called 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 you 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 problem, said Shokat, comes down to the
fact 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
bravely face, finding ways of minimizing this toxicity is a big goal
pharmaceutical companies would like to solve. Shokat and his colleagues believe
the shotgun approach is one way to do this.
The
dogma that the best drugs are the most selective could be wrong, he said, and
for cancer a
magic shotgun may be more effective than a magic bullet.
Looking
at fruit flies, they found a way to screen compounds to find the few that best
disrupt an entire network of interacting genes and proteins. Rather than
judging a compound according to how well it inhibits a specific target, they
judged as best the compounds that inhibited not only that specific target but
disrupted other parts of the network while not interacting with other genes and
proteins that would cause toxic side effects.
More
information: The
article, "Chemical genetic discovery of targets and anti-targets for
cancer polypharmacology" by Arvin C. Dar, Tirtha K. Das, Kevan M. Shokat
and Ross Cagan appears in the June 7, 2012 issue of the journal Nature. See: http://dx.doi.org/
… /nature11127
Provided
by University
of California, San Francisco
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