Locked up tight. STI-571 drug (yellow) binds the inactive form of the Abl protein, shown at left. But as shown at right, the drug does not match the active form of Src, another oncogenic kinase.
The researchers discovered how a promising drug acts on cancer as a smart bomb, homing in a very narrow range of potential targets in the cell. The compound, known as STI-571 has shown remarkable success in early clinical trials in patients with chronic myeloid leukemia (CML). To know more details on the mode of action could contribute to the design of similar weapons against cancer. "It is a very neat story," says cell biologist Tony Hunter of the Salk Institute for Biological Studies in La Jolla, California.
STI-571 was identified in the early 190s by scientists Novartis pharmaceutical company, and then shown to block the enzyme produced by abl a so-called oncogene whose overactivity is thought to cause the massive proliferation of leukemia cells in patients with CML. in line with this clinical trials conducted to date have shown that STI-571, in sufficient doses, can cause the apparent disappearance of leukemic cells from the patient's blood and treatment side effects are relatively mild. But there was a break -tête. Abl protein kinases belong to a large family of enzymes that transfer a phosphate group from ATP to the protein. What was unknown is why STI-571 has such a limited range of action. In addition to Abl, it only blocks two other kinases of the 50 or so proteins tested -. Which may be why it has so few side effects
To explore the basis of the specificity of STI-571, John Kuriyan and Thomas Schindler of Rockefeller University in New York and colleagues crystallized the catalytic region of human Abl protein with a version of STI-571. They then used X-ray crystallography to determine the three dimensional structure of the complex drug-protein. Abl kinases like many others, does not begin in action until a phosphate is added to the "activation loop." This step changes the shape or conformation of the enzyme, the opening of so that the kinase can bind to ATP and its target proteins. what reveals the crystal structure, the team reports in the September 15 issue of Science is as STI-571 binds to the inactive conformation of Abl, effectively locking the activation phosphate.
the discovery also explains why so few other kinases are inhibited by the drug. "When kinases are assets, they are very similar, "said Kuriyan." But when they are off, they can be very different from each other. " He noted that drug developers usually try to inhibit active enzymes. But kinases, inactive forms can make better targets, said Kuriyan. Meanwhile, clinical trials are ongoing to see if the early promise of CML supports.
Related Sites
The Kuriyan laboratory at Rockefeller
Information on Leukemia National Cancer Institute
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