Published November 1, 2013 - More info
Targeting kinases is central to drug-based cancer therapy but remains challenging because the drugs often lack specificity, which may cause toxic side effects. Modulating side effects is difficult because kinases are evolutionarily and hence structurally related. The lack of specificity of the anticancer drug imatinib enables it to be used to treat chronic myeloid leukemia, where its target is the Bcr-Abl kinase, as well as a proportion of gastrointestinal stromal tumors (GISTs), where its target is the C-Kit kinase. However, imatinib also has cardiotoxic effects traceable to its impact on the C-Abl kinase. Motivated by this finding, we made a modification to imatinib that hampers Bcr-Abl inhibition; refocuses the impact on the C-Kit kinase; and promotes inhibition of an additional target, JNK, a change that is required to reinforce prevention of cardiotoxicity. We established the molecular blueprint for target discrimination in vitro using spectrophotometric and colorimetric assays and through a phage-displayed kinase screening library. We demonstrated controlled inhibitory impact on C-Kit kinase in human cell lines and established the therapeutic impact of the engineered compound in a novel GIST mouse model, revealing a marked reduction of cardiotoxicity. These findings identify the reengineered imatinib as an agent to treat GISTs with curbed side effects and reveal a bottom-up approach to control drug specificity.
Ariel Fernández, Angela Sanguino, Zhenghong Peng, Eylem Ozturk, Jianping Chen, Alejandro Crespo, Sarah Wulf, Aleksander Shavrin, Chaoping Qin, Jianpeng Ma, Jonathan Trent, Yvonne Lin, Hee-Dong Han, Lingegowda S. Mangala, James A. Bankson, Juri Gelovani, Allen Samarel, William Bornmann, Anil K. Sood, Gabriel Lopez-Berestein
Original citation: J. Clin. Invest. 2007;117(12):4044–4054. doi:10.1172/JCI32373.
Citation for this corrigendum: J. Clin. Invest. 2013;123(11):4980. doi:10.1172/JCI73378.
During the preparation of this manuscript, information regarding an NIH grant was omitted from the Acknowledgments. The correct Acknowledgments section is below.
The research of A. Fernández was supported by NIH grant R01 GM072614 and by a grant from the Gulf Coast Center for Computational Cancer Research. J. Ma acknowledges support from the Welch Foundation. G. Lopez-Berestein acknowledges support from CA. A.K. Sood acknowledges support from the University of Texas MD Anderson Cancer Center SPORE in ovarian cancer (P50CA83639) and a Program Project Development Grant from the Ovarian Cancer Research Fund Inc. The GIST882 cells were a gift from Jonathan Fletcher, Dana-Farber Cancer Institute–Harvard Medical School. The experimental findings reported in Figure 5 validating the theoretical results in the paper were obtained in compliance with the aims and collaborative agreements with Eli Lilly and Co. specified in the NIH/NIGMS grant R01GM072614 (A. Fernandez, principal investigator).
The authors regret the error.