Next-era targeted therapy overcoming Gleevec's shortcomings

Anaheim, Calif. -- Though Gleevec has shown "wonder drug" capabilities for treating chronic myelogenous leukemia and other cancers, experience in treating patients has revealed some shortcomings. In some cases, patients have undergone relapse after building a resistance to the drug. For others with advanced disease, the drug has failed to produce durable remissions.

However, a molecular understanding of resistance has rapidly led to a new generation of drugs that might prove more effective than Gleevec.

Two studies presented here at the 96th Annual Meeting of the American Association for Cancer Research report that a new compound, known as AMN107, may one day offer a more potent alternative for treating patients with acquired Gleevec resistance and others with advanced CML.

As originally conceived, Gleevec works in CML patients by selectively deactivating Bcr-Abl, the abnormal tyrosine kinase protein that triggers rapid growth of leukemic cells. Gleevec was hailed as the first approved drug to directly inhibit the activity of an enzyme known to cause uncontrolled cell growth, and it has been highly successful for many patients.

Scientists soon recognized, however, that some patients develop mutations in the Bcr-Abl protein that drastically reduce Gleevec's effectiveness.

AMN107 Holds Promise for Treating Gleevec-Resistant Leukemia According to Oregon Scientists: Abstract 5282

To overcome resistance to Gleevec, scientists are designing new compounds that bind tighter to the intended target, the Bcr-Abl protein. One such candidate drug is AMN107, synthesized by Novartis Pharmaceuticals in Basel, Switzerland, and characterized in collaboration with investigators at the Dana Farber Cancer Institute.

In essence, AMN107 retains half the chemical makeup of Gleevec, while the other half was engineered to assure a tighter link to Bcr-Abl, thus increasing potency and potentially overcoming resistance due to mutations

Contact: Warren R. Froelich
American Association for Cancer Research

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