Hybrid Compound Design To Overcome the Gatekeeper T338M Mutation in cSrc
Hybrid Compound Design To Overcome the Gatekeeper T338M Mutation in cSrc
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DOI：
10.1021/jm9002928
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发表时间：
2009-07-09
影响因子：
7.3
通讯作者：
Rauh, Daniel
中科院分区：
文献类型：
--
作者：
Getlik, Matthaeus;Gruetter, Christian;Rauh, Daniel
耐药性的出现仍然是开发长期有效的激酶抑制剂的根本挑战。结合到位于高度保守的ATP口袋之外的位点的变构抑制剂被认为比ATP竞争性抑制剂更具选择性，并且可以规避某些耐药机制。与酪氨酸激酶cSrc复合的I型和变构III型抑制剂的晶体结构使我们能够采用基于结构的设计原理将这些支架开发成有效的II型激酶抑制剂。这些化合物之一，3c（RL46），通过直接抑制cSrc破坏癌细胞中FAK介导的粘着斑。从晶体结构中收集的细节揭示了这些化合物的一个子集的关键特征，在看门人残基附近具有令人惊讶的灵活性，使这些化合物能够克服cSrc中出现的dasatinib耐药看门人突变。
The emergence of drug resistance remains a fundamental challenge in the development of kinase inhibitors that are effective over long-term treatments. Allosteric inhibitors that bind to sites lying Outside the highly conserved ATP pocket are thought to be more selective than ATP-competitive inhibitors and may circumvent some mechanisms of drug resistance. Crystal structures of type I and allosteric type III inhibitors in complex with the tyrosine kinase cSrc allowed us to employ principles of structure-based design to develop these scaffolds into potent type II kinase inhibitors. One of these compounds, 3c (RL46), disrupts FAK-mediated focal adhesions in cancer cells via direct inhibition of cSrc. Details gleaned from crystal structures revealed a key feature of a subset of these compounds, a surprising flexibility in the vicinity of the gatekeeper residue that allows these compounds to overcome a dasatinib-resistant gatekeeper mutation emerging in cSrc.