Editing Drugs to Curb Side Effects

Context-dependent functionalities introduce a risk of toxicity in molecular target therapy [4-7], For example, the constitutively active chimera Bcr-ABL kinase is a clinical target for treating chronic myeloid leukemia (CML), as evidenced by the success of the KI imatinib (Gleevec) [18], but ABL inhibition in cardiomyocytes (off-target cells in CML treatment) may introduce a cardiotoxicity risk [5-7], as shown in Fig. 12.1. This risk is more pronounced for promiscuous KIs like sunitinib [5, 8], 

In general, prevention of side effects arising from context dependence requires tissue-specific delivery [15-17] to selectively avoid inhibiting a target kinase in off-target cells. In practice, this level of selectivity is difficult to achieve. In view of this problem, we propose a two-component treatment in which one drug modulates a downstream component of the toxicity-signaling pathway recruited by the other. 

Two-component treatments have been exploited to improve therapeutic impact [19-21], In this chapter we advocate an alternative application with the aim of 

12 Wrapper Drugs as Therapeutic Editors of Side Effects 

We focus on editing cardiotoxicities of KIs, which are significant side effects [5-8] and fulfill the applicability premises described above (cf. Fig. 12.1). In general, KI cardiotoxicity remains a controversial subject [5-8, 22, 23], However, 

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