Volume 1, Issue 4
Flipping The Switch On Cancer
Four years ago, a new weapon in the war on cancer made it to clinical trials accompanied by headlines and hope. Gleevec, a drug manufactured by Novartis, appeared to selectively turn off a specific cancer-causing protein like a light switch, stopping the progress of a severe form of leukemia in its tracks. The odd thing is that nobody really knew how the drug knocked out the leukemia-causing cells while leaving healthy proteins alone. Just seven months before the FDA approved Gleevec in May 2001, Professor John Kuriyan announced that he had solved the puzzle.
"Our lab studies protein molecules that are produced by certain genes, normal or not," says Kuriyan, a professor of molecular and cell biology and chemistry at UC Berkeley. "By determining how the atoms are arranged in three dimensions, we try to figure out what goes wrong as a result of particular mutations. That can help drug companies learn how a compound might flip the switch one way or another."
John Kuriyan is also affiliated with the California Institute for Quantitative Biomedical Research, a cooperative effort among UC Berkeley, UC Santa Cruz, and UC San Francisco.
At the time of his discovery, Kuriyan was head of the Laboratory of Molecular Biophysics at Rockefeller University and an investigator at the Howard Hughes Medical Institute (HHMI). Since arriving at Berkeley, Kuriyan has continued his cancer-related research with HHMI support. Most recently, he's helped determine why some patients develop a resistance to Gleevec.
Gleevec's ability to fight chronic myelogenous leukemia (CML) first emerged from drug discovery techniques based on trial-and-error. Pharmaceutical companies commonly screen myriad compounds and then use organic chemistry to optimize those that show promise as potential drugs.
When Gleevec came on the scene, it was well known that CML is caused when a single molecule called the Abelson kinase (Abl) is activated. The tyrosine kinase family, of which Abl is a member, play a key role in regulating cell growth and division. When genetic mutations occur that disrupt the normal switching function of Abl, the cells divide out of control, leading to cancer.
"The switch is not statically locked on or off, but the disease is caused when it's on much more often than it's off," says Kuriyan, also a faculty scientist at Lawrence Berkeley National Laboratory.
Drugs work by binding to the protein and disrupting its function. However, the human genome codes for about 500 protein kinases that are virtually identical. Flipping the right switch is tricky.
"When the kinases are ready to work, they all look the same," Kuriyan says. "That's because they bring to bear the same machinery to carry out their chemical reactions."
As a result, it's extremely difficult to find a drug candidate that targets a certain type of a protein kinase--Abl, in the case of chronic myelogenous leukemia--and not other normal kinases. But Gleevec did just that. The big question was how.
Kuriyan and his colleagues are masters of X-ray crystallography, a method used to reconstruct a three-dimensional image of a molecule. This kind of visual analysis revealed that Gleevec didn't recognize the "on" state of the protein but rather the "off" state. When the proteins are "on," they do indeed look alike. But when "off," the differences are dramatic.
This model, built from X-ray diffraction data, depicts the crystal structure of the Abelson kinase in complex with the Gleevec molecule.
"Evolution has specialized these switching devices so they all come into the same shape when they turn on," Kuriyan says. "But when they turn off in response to the presence or absence of a certain input signal, they're structurally quite different. Gleevec takes advantage of that to bind to just a few of the kinases it encounters instead of all 500."
Since unraveling the secret of Gleevec's power, Kuriyan and his colleagues continue to explore the intricate workings of the molecular switches. For example, Gleevec is entirely ineffective for a growing number of patients. Certain mutations, Kuriyan says, entirely block the drug from binding to the kinase.
"Unfortunately what we're realizing is that the property that gives these compounds their specificity is also an Achilles' Heel for the drug," he says. "To evade the drug, all the protein has to do is destabilize the inactive state."
To that end, Kuriyan, in collaboration with HHMI investigator Charles L. Sawyers at the University of California, Los Angeles, is examining new "sloppier inhibitors" that aren't quite as dependent on recognizing Abl's "off" state to work. So far, one new drug, developed by Bristol-Myers Squibb, has proven effective in mice and is undergoing FDA Phase I clinical trials.
"We hope to understand the origins of resistance," Kuriyan says. "Perhaps the very basic information we provide will help the pharmaceutical companies design the next generation of anti-cancer drugs."
http://www.boingboing.net/images/Abl.jpg This model, built from X-ray diffraction data, depicts the crystal structure of the Abelson kinase in complex with the Gleevec molecule.