Fragment-based modification of 2,4-diarylaminopyrimidine derivatives as ALK and ROS1 dual inhibitors to overcome secondary mutants
Fragment-based modification of 2,4-diarylaminopyrimidine derivatives as ALK and ROS1 dual inhibitors to overcome secondary mutants
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基于片段的 2,4-二芳基氨基嘧啶衍生物修饰作为 ALK 和 ROS1 双重抑制剂以克服克唑替尼耐药突变体
DOI：
10.1016/j.bmc.2020.115719
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发表时间：
2020-10-15
影响因子：
3.5
通讯作者：
Zhai, Xin
中科院分区：
文献类型：
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作者：
Zhu, Minglin;Li, Wei;Zhai, Xin
为了探索能够克服克唑替尼耐药突变体的新型 ALK 和 ROS1 双抑制剂，设计、合成了两个系列的 2,4-二芳基氨基嘧啶衍生物，并评估了其体外细胞毒活性。在这项工作中，我们保留了2,4-二芳基氨基嘧啶支架，并用磺酰基和丙烯酰胺部分衍生化了DAAP支架，以扩展构效关系（SAR）研究。令我们高兴的是，一些化合物在 MTT 测定中表现出优异的抑制活性，达到两位数纳摩尔水平。选择四种化合物进一步进行酶测定，结果鉴定出有效的 ALK 和 ROS1 双重抑制剂 X-17，对 ALK、ALK(L1196M)、ALK(G1202R) 和 ROS1 的 IC50 值分别为 3.7 nM、2.3 nM、8.9 nM 和 1.9 nM。最终，X-17 的分子对接研究清楚地揭示了与 ALK 合理且最佳的结合相互作用。
In order to explore novel ALK and ROS1 dual inhibitors capable of overcoming crizotinib-resistant mutants, two series of 2,4-diarylaminopyrimidine derivatives were designed, synthesized and evaluated for their in vitro cytotoxic activity. In this work, we retained the 2,4-diarylaminopyrimidine scaffold and derivatize the DAAP scaffold with sulfonyl and acrylamide moieties to extend the structure-activity relationship (SAR) study. To our delight, some compounds exhibited excellent inhibitory activity with a double-digit nanomolar level in MTT assay. Four compounds were selected for enzymic assays further, the results led to the identification of a potent ALK and ROS1 dual inhibitor X-17, with IC50 values of 3.7 nM, 2.3 nM, 8.9 nM and 1.9 nM against ALK, ALK(L1196M), ALK(G1202R) and ROS1, respectively. Ultimately, the molecular docking studies on X-17 clearly disclosed reasonable and optimal binding interactions with ALK.