Epistructural Re-engineering of Imatinib to Eliminate Adverse Side Effects

Abstract

Molecular cancer treatments are often geared at interfering with signaling pathways that govern cell fate or proliferation. These therapeutic strategies target kinases, the signal transducers in the cell. This approach remains challenging because kinases are evolutionarily and therefore structurally related and thus kinase inhibitors often lack the required specificity, which may lead to toxic or health-threatening side effects. This chapter illustrates the power of the wrapping concept in engineering safer kinase inhibitors, thus unraveling a rational approach to fulfill this therapeutic imperative. The focus of this chapter is the redesign of the anticancer drug imatinib (Gleevec) used to treat chronic myeloid leukemia, where its primary target is the chimeric Bcr-Abl kinase, as well as certain solid tumors based on its impact on the C-Kit kinase. Imatinib also has potentially cardiotoxic effects traceable to its impact on the Abl kinase in off-target cells, and immunosuppressive effects through its impact on Lck. This chapter describes a wrapping modification of imatinib purposely designed to prevent inhibitory impact against Abl (and Bcr-Abl) and Lck, to re-focus the impact towards C-Kit and to promote inhibition of an additional target, JNK, required to reinforce the prevention of cardiotoxicity and recognized as a target of significant therapeutic interest in its own right. The molecular blueprint for target discrimination, described in Chaps. 4 and 6, is now validated through assays that span a vast testing ground, from in silico assessment and test-tube probes to animal models. The findings surveyed in this chapter identify the wrapping-based re-engineered imatinib as an agent to treat gastrointestinal stromal tumors and possibly ovarian cancer with reduced side effects, thereby illustrating the therapeutic impact of the wrapping technology.