Structural reengineering of imatinib to decrease cardiac risk in cancer therapy.
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.
Demetri
George D
GD
Ludwig Center for Cancer Research, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02115, USA. gdemetri@partners.org
D000818:Animals; D001549:Benzamides; D054715:Cardiotoxins / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D016044:Fusion Proteins, bcr-abl; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000201:enzymology*; D006331:Heart Diseases / Q000139:chemically induced / Q000201:enzymology; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000201:enzymology; D010879:Piperazines / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D011743:Pyrimidines / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D001549:Benzamides; D054715:Cardiotoxins; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D019009:Proto-Oncogene Proteins c-kit; D016044:Fusion Proteins, bcr-abl; D048670:MAP Kinase Kinase 4