Structural reengineering of imatinib to decrease cardiac risk in cancer therapy

Abstract

Imatinib, a selective, small-molecule tyrosine kinase inhibitor, has life-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, Fernández 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 WBZ_4 compared with imatinib via the inhibition of JNK. The study shows that structural reengineering of a kinase-inhibitory drug to improve tolerability while preserving efficacy is feasible.

Figure 1. Structural modification of imatinib allows retention of its anticancer activity without cardiotoxic effects.

(A) Imatinib is able to bind to the ATP-binding pocket of tyrosine kinases and therefore block the mutant KIT receptor tyrosine kinase activity in GIST cells, leading to inhibition of intracellular signaling, decreased cell proliferation, and apoptosis of the cancer cells. Cardiac myocytes exhibit normal signaling through the intracellular ABL kinase. Imatinib-mediated inhibition of the ABL kinase results in decreased cardiac myocyte function. (B) Imatinib serves as a ligand that binds to the ATP-binding pocket of KIT as well as ABL kinases. In this issue of the JCI, Fernández et al. (13) examined the de-wetting profiles of KIT and BCR-ABL and reengineered imatinib to create WBZ_4. This compound was designed to retain binding to KIT ATP-binding pockets, not to bind ABL, and to bind to and inhibit JNK kinase for the purpose of increased cardioprotection.