Discovery of novel 2,4-diarylaminopyrimidine analogues (DAAPalogues) showing potent inhibitory activities against both wild-type and mutant ALK kinases
Discovery of novel 2,4-diarylaminopyrimidine analogues (DAAPalogues) showing potent inhibitory activities against both wild-type and mutant ALK kinases
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发现新型 2,4-二芳基氨基嘧啶类似物 (DAAPalogues)，对野生型和突变型 ALK 激酶均具有有效的抑制活性
DOI：
10.1021/jm5005144
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发表时间：
2015
影响因子：
7.3
通讯作者：
Zhang Ao
中科院分区：
文献类型：
--
作者：
Song Zilan;Yang Yanhong;Liu Zhiqing;Peng Xia;Guo Junfeng;Yang Xinying;Wu Kui;Ai Jing;Ding Jian;Geng Meiyu;Zhang Ao
我们已经开发了一系列新的2，4-二芳基氨基嘧啶类似物（DAAPalogues），带有一个灵活的氨基酸侧链，不同于大多数文献报道的ALK抑制剂，通常具有结构受限的芳基哌嗪片段或其等效物在溶剂相互作用区域。在ALK野生型和门控突变体L1196 M酶测定中，广泛的结构阐述导致化合物15的IC 50值分别为2.7和15.3 nM。该化合物不仅对不同致癌形式的ALK成瘾细胞表现出高度增殖抑制作用，而且还有效抑制了几种ALK继发突变细胞，包括看门人L1196 M和F1174 L。在ALK驱动的SUP-M2异种移植模型中实现了显著的抗肿瘤疗效。
We have developed a series of new 2,4-diarylaminopyrimidine analogues (DAAPalogues) bearing a flexible amino acid side chain, different from the majority of the literature reported ALK inhibitors that often possess a structurally constrained arylpiperazine fragment or its equivalents in the solvent-interaction region. Extensive structural elaboration led to compound15possessing IC50values of 2.7 and 15.3 nM, respectively, in the ALK wild-type and gate-keeper mutant L1196M enzymatic assays. This compound not only showed high proliferative inhibition against ALK-addicted cells across different oncogenic forms but also effectively suppressed several ALK secondary mutant cells, including the gate-keeper L1196M and F1174L. Significant antitumor efficacy was achieved in the ALK-driven SUP-M2 xenograft model.