c-Met inhibitors with different binding modes - Two is better than one
c-Met inhibitors with different binding modes - Two is better than one
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DOI：
10.4161/cc.7.9.5827
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发表时间：
2008-05-01
期刊：
影响因子：
4.3
通讯作者：
Bellon, Steven F.
中科院分区：
文献类型：
--
作者：
Dussault, Isabelle;Bellon, Steven F.
由于靶点的预先存在的突变或由于治疗选择而产生的突变而对激酶抑制剂产生的原发性和获得性耐药现在是用这些药物治疗的癌症患者的常见主题。针对同一靶标的不同类别的抑制剂已经成功地克服了这些抗性机制，至少暂时地克服了这些抗性机制，因为它们能够与突变的受体相互作用。因此，针对给定靶点使用不同类别的抑制剂可能会为癌症患者提供更多的治疗选择。c-Met抑制剂正在成为潜在的重要的新型癌症药物，并且已经开始对这些药物进行针对几种突变受体的分析。我们最近鉴定了对野生型和突变的c-Met变体有活性的c-Met抑制剂。X射线晶体学显示，这类抑制剂与c-Met的结合方式与另一种c-Met抑制剂非常不同，后者对某些c-Met突变体显示出原发性耐药。我们的结果表明，有可能鉴定出对一系列c-Met突变具有活性的c-Met抑制剂。
Primary and acquired resistance to kinase inhibitors due to preexisting mutations of the target or to mutations that arise as a result of selection by therapy is now a common theme in cancer patients treated with these drugs. Different classes of inhibitors for the same target have been successful in overcoming, at least temporarily, these resistance mechanisms because of their ability to interact with the mutated receptor. Therefore, having different classes of inhibitors for a given target might offer more treatment options for cancer patients. c-Met inhibitors are emerging as potentially important new cancer drugs and profiling these agents against several mutant receptors has begun. We have recently identified c-Met inhibitors that are active against wild-type and mutated c-Met variants. X-ray crystallography revealed that this class of inhibitors binds c-Met very differently than another c-Met inhibitor that shows primary resistance to some c-Met mutants. Our results suggested that it is possible to identify c-Met inhibitors that will be active against a range of c-Met mutations.