Through X-ray crystallographic studies, Ariad says its study shows 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 explains 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 chronic myeloid leukemia (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.
Tim Clackson, chief scientific officer, said: “There is a growing unmet medical need for new treatment options for CML patients who no longer are responding to first and second generation targeted therapies or have become intolerant to these treatments. This detailed structural analysis of the T315I mutation was a critical step in our effort to design a new targeted therapy for leukemia. These data support our ongoing plans to develop AP24534 in various forms of leukemia and to file an investigational new drug application for AP24534 later this year.”