Bcr-Abl Kinase Inhibitors

Abstract

The hallmark of chronic myelogenous leukemia (CML) is the expression of Bcr-Abl, a constitutivelyactive form of the Abl tyrosine kinase. Imatinib, a 2-phenyl aminopyrimidine Bcr-Abl inhibitor developedby Novartis and marketed under the tradename of Gleevec (Glivec), is highly effective in treating CML patientswith early stage disease. However, patients with advanced disease often become resistant to imatinib. Thepredominant form of this resistance is the development of mutations in the Bcr-Abl protein. These pointmutations can be amino acid residues that make direct contact with imatinib or residues that do not allowBcr-Abl to adopt the inactive conformation. Since imatinib can only bind to the inactive conformation ofthe protein, both types of mutations prevent this inhibitor from binding. Several approaches have beentaken to identify additional Bcr-Abl inhibitors including: (1) more potent analogs of imatinib; (2) non-ATPcompetitive inhibitors of Bcr-Abl; and (3) dual inhibitors of both Bcr-Abl and members of the Src familyof kinases (SFKs) that bind to the active form of Bcr-Abl. The progress made on the development of thesenew agents, including compounds with activity against the highly resistant T315I mutation of Bcr-Abl, willbe discussed.