Abstract：
Ponatinib is a multi-target tyrosine kinase inhibitor that targets ABL, SRC, FGFR, and so on. It was designed to overcome the resistance of BCR-ABL mutation to imatinib, especially the gatekeeper mutation ABLT315I. The molecular mechanism by which ponatinib overcomes mutations of BCR-ABL and some other targets has been explained, but little information is known about the characteristics of ponatinib binding to SRC. Here, we showed that ponatinib inhibited wild type SRC kinase but failed to inhibit SRC gatekeeper mutants in both biochemical and cellular assays. We determined the crystal structure of ponatinib in complex with the SRC kinase domain. In addition, by structural analysis, we provided a possible explanation for why ponatinib showed different effects on SRC and other kinases with gatekeeper mutations. The resistance mechanism of SRC gatekeeper mutations to ponatinib may provide meaningful information for designing inhibitors against SRC family kinases in the future.
摘要：
Ponatinib是一种靶向ABL的多靶点酪氨酸激酶抑制剂，SRC,FGFR,等等。它旨在克服BCR-ABL突变对伊马替尼的抗性，尤其是看门人突变ABLT315I。ponatinib克服BCR-ABL突变和其他一些靶点的分子机制已经得到解释。但有关普纳替尼与SRC结合的特征的信息很少。这里,我们显示,在生化和细胞试验中,普纳替尼抑制野生型SRC激酶,但未能抑制SRC看门人突变体.我们确定了与SRC激酶结构域复合的ponatinib的晶体结构。此外,通过结构分析，我们提供了一个可能的解释,解释了为什么ponatinib对SRC和其他有看门人突变的激酶有不同的作用.SRC看门人突变对ponatinib的耐药机制可能为将来设计针对SRC家族激酶的抑制剂提供有意义的信息。
