New Study by ARIAD Scientists Offers Insights into Design of Small-Molecule Drugs to Treat Drug-Resistant Leukemia
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ARIAD Pharmaceuticals, Inc. has announced publication, for the first time, of the high-resolution structure of the protein responsible for one of the major clinically relevant genetic variants of drug-resistant chronic myeloid leukemia (CML).
These findings by a team of ARIAD scientists were used to guide the design of ARIAD’s oral multi-targeted kinase inhibitor, AP24534, for use in CML and other cancers. The findings were published in the September issue of Chemical Biology and Drug Design. ARIAD plans to file an investigational new drug application for AP24534 by the end of this year to begin clinical trials.
CML is a slowly progressing cancer in which too many white blood cells are made in the bone marrow. In most cases, a genetic abnormality involving the Bcr-Abl protein, a tyrosine kinase encoded by the Philadelphia chromosome, results in constantly activated growth of cancer cells.
Through X-ray crystallographic studies, this study showed in detail how inhibitors of the Bcr-Abl protein, such as AP24534, are able to overcome the structural changes induced by the T315I mutation and bind to the mutated form of the protein.
The data also explain why the first-generation Bcr-Abl inhibitor, imatinib, and second-generation Bcr-Abl inhibitors, such as dasatinib and nilotinib, are not able to inhibit this key genetic variant and thus are not effective against all forms of CML.
In contrast to these first- and second-generation Bcr-Abl inhibitors, AP24534 potently blocks all clinically relevant forms of the Bcr-Abl protein, including the unmutated protein (the target of imatinib), the commonly mutated proteins (the targets of dasatinib and nilotinib), and the T315I mutated protein.
The Bcr-Abl T315I mutation currently accounts for 15 to 20 percent of all drug resistance in CML. The prevalence of the T315I mutation is increasing as patients relapse after treatment with current second-generation inhibitors.
