Structural reengineering of imatinib to decrease cardiac risk in cancer therapy

Imatinib, a selective, small-molecule tyrosine kinase inhibitor, has fife-saving clinical activity in certain cancers, but questions have been raised about the potential for cardiac toxicity through inhibition of its target, ABL kinase. In this issue of the JCI, Fernandez et al. describe a novel method by which the ABL-inhibitory activity of imatinib was deleted by modifying its chemical structure (see the related article beginning on page 4044). The anticancer activity of the reengineered agent, called WBZ_4, was instead preserved against gastrointestinal stromal tumors in both in vitro and in vivo models via inhibition of KIT tyrosine kinase, and the desired safety was demonstrated with less cardiotoxicity of V.7BZ_4 compared with imatinib via the inhibition of JNK. The study shows that structural reengineering of a kinaseinhibitory drug to improve tolerability while preserving efficacy is feasible.