An anticancer C-Kit kinase inhibitor is reengineered to make it more active and less cardiotoxic
An anticancer C-Kit kinase inhibitor is reengineered to make it more active and less cardiotoxic
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DOI：
10.1172/jci32373
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发表时间：
2007-12-01
影响因子：
15.9
通讯作者：
Lopez-Berestein, Gabriel
中科院分区：
文献类型：
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作者：
Fernandez, Ariel;Sanguino, Angela;Lopez-Berestein, Gabriel
靶向激酶是基于药物的癌症治疗的核心，但仍然具有挑战性，因为药物往往缺乏特异性，这可能会导致毒副作用。调节副作用是困难的，因为激酶在进化上是相关的，因此在结构上是相关的。抗癌药物伊马替尼缺乏特异性，使其能够用于治疗慢性髓性白血病，其靶点是Bcr-Abl激酶，以及一部分胃肠道间质瘤（GIST），其靶点是C-Kit激酶。然而，伊马替尼也有心脏毒性作用，可追溯到其对C-Abl激酶的影响。受这一发现的启发，我们对伊马替尼进行了修改，阻碍了Bcr-Abl抑制;重新关注对C-Kit激酶的影响;并促进对另一个靶点JNK的抑制，这是加强预防心脏毒性所需的变化。我们利用分光光度法和比色法以及噬菌体展示激酶筛选文库建立了体外靶点识别的分子蓝图。我们证明了对人细胞系中C-Kit激酶的受控抑制作用，并在新型GIST小鼠模型中建立了工程化合物的治疗作用，揭示了心脏毒性的显著降低。这些发现确定了重新设计的伊马替尼作为治疗GIST的药物，副作用得到抑制，并揭示了一种自下而上的方法来控制药物特异性。
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.