Novel agents to override imatinib resistance mechanisms

Abstract

Chronic myelogenous leukemia (CML) is a disorder of hematopoietic stem cells that results from the Philadelphia chromosome (Ph) created through translocation of human chromosomes 9 and 22. The resulting Bcr‐Abl fusion protein has constitutively high tyrosine kinase activity that causes transformation of hematopoietic stem cells. Imatinib mesylate (IM) was developed as a specific Bcr‐Abl kinase inhibitor and is efficacious in treating Ph‐chromosome‐positive (Ph+) leukemias such as CML and Ph+ acute lymphoblastic leukemia (ALL). Within a few years of its introduction to the clinic, IM has dramatically altered the first‐line therapy for CML. Although most newly diagnosed CML patients in the chronic phase (CP) achieved durable responses when treated with IM, resistance to IM has become a major problem in patients with advanced‐stage disease. The most important mechanism of IM resistance are point mutations within the Abl kinase domain; therefore, there is an urgent need for novel agents that can inhibit mutated Bcr‐Abl. In this review, we describe novel Bcr‐Abl tyrosine kinase inhibitors, the so‐called “Super Gleevec” inhibitors. Drug Dev Res 69:398–406, 2008. © 2008 Wiley‐Liss, Inc.