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Study finds new designer drug is potent treatment for chronic myelogenous leukemia

BOSTON--A laboratory study led by researchers at Dana-Farber Cancer Institute has shown that a potent and highly selective therapy for chronic myelogenous leukemia (CML) may ultimately be more effective than Gleevec, the current standard of care. 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. Discovered by and in development with Novartis Pharma AG, AMN107 is a small molecule tyrosine kinase inhibitor.

"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.

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, and patients can develop a resistant type of Bcr-Abl that no longer binds to Gleevec at all.

Using rational drug design 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.

Data from the study published in Cancer Cell showed that in experiments with laboratory samples of CML cells, AMN107 killed the cells more effectively than Gleevec. In follow-up studies with mice with a human form of CML, AMN107 produced lengthier remissions than Gleevec and triggered remissions in animals in which the disease had become resistant to Gl
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Contact: Bill Schaller
617-632-4090
Dana-Farber Cancer Institute
18-Feb-2005


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