"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
william_schaller@dfci.harvard.edu
617-632-5357
Dana-Farber Cancer Institute
14-Feb-2005