BOSTON--Using rational drug design strategies, investigators at Dana-Farber Cancer Institute and Novartis Pharmaceuticals in Basel, Switzerland have created a targeted therapy for chronic myelogenous leukemia (CML) that may ultimately be more effective than Gleevec, the current frontline treatment. The researchers report in the February issue of Cancer Cell that the new compound, AMN107, is about 20 times more potent than Gleevec and is effective in treating Gleevec-resistant disease in model systems.
"While Gleevec represents a major treatment advance for CML approximately 95 percent of patients treated with Gleevec achieve remission there clearly is a need for therapies that produce longer remissions, are active against advanced disease, and can be used when Gleevec loses effectiveness," says Dana-Farber's James Griffin, MD, senior author of the study. "The goal of this study was to develop a drug that hits the same target on CML cells as Gleevec does, and to hit more of the target."
Gleevec shuts down CML by blocking the function of Bcr-Abl, the abnormal tyrosine kinase protein in the leukemic cells that causes them to grow too quickly. However, it does not bind very tightly to this protein, takes a long time to induce remissions, and patients can develop a resistant type of Bcr-Abl that no longer binds to Gleevec at all.
To circumvent these shortcomings, researchers at Novartis determined the crystal structure of Bcr-Abl, and then constructed compounds that would lock into the receptor more securely than Gleevec. Investigators at Dana-Farber tested the new compounds to measure their effectiveness against CML in laboratory cell cultures and mice with the disease.
The final product was AMN107, a half-new, half-old hybrid. Half of AMN107's chemical makeup is identical to a portion of Gleevec, the remainder is completely different, explains Griffin, who is also a professor of medicine at Harvard Medical School.
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Contact: Bill Schaller
Dana-Farber Cancer Institute
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