Design, synthesis and biological evaluation of 2-arylaminopyrimidine derivatives bearing 1,3,8-triazaspiro[4,5]decan-4-one or piperidine-3-carboxamide moiety as novel Type-I1/2 ALK inhibitors
Design, synthesis and biological evaluation of 2-arylaminopyrimidine derivatives bearing 1,3,8-triazaspiro[4,5]decan-4-one or piperidine-3-carboxamide moiety as novel Type-I1/2 ALK inhibitors
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带有 1,3,8-三氮杂螺[4,5]癸-4-酮或哌啶-3-甲酰胺部分的 2-芳氨基嘧啶衍生物作为新型 I1/2 ALK 抑制剂的设计、合成和生物学评价
DOI：
10.1016/j.bioorg.2019.103456
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发表时间：
2020
影响因子：
5.1
通讯作者：
Xin Zhai
中科院分区：
文献类型：
--
作者：
Xiuqi Miao;Lingyun Xing;Ming Guo;Hong Zhang;Sicong Liu;Shiliang Yin;Ping Gong;Dajun Zhang;Xin Zhai
为了开发新型ALK I1/2型抑制剂，克服广泛的耐药突变，特别是ATP口袋周围的L1196 M突变，基于骨架跳跃设计了两个系列的2-芳氨基嘧啶衍生物（11 a-fan和22 a-t）。广泛的结构阐述发现化合物22 o对ALK阳性的Karpas 299和H2228细胞系分别具有0.06和0.23 μM的极好的IC 50值。同时，22 o在ALKWT（2.5 nM）和ALKL 1196 M（6.5 nM）酶促测定中显示出令人鼓舞的抑制效力。AO/EB和Hoechst 33258实验结果表明，22 oc可诱导细胞凋亡，且呈剂量依赖性。最终，22 o与ALK的分子对接清晰地呈现了活性位点内的重要相互作用，符合I1/2型抑制剂结合模式。
Aiming to develop novel Type-I1/2inhibitors of ALK to overcome extensive resistance mutations, especially the L1196M mutation surrounding the ATP pocket, two series of 2-arylaminopyrimidine derivatives (11a-fand22a-t) were designed based on scaffold hopping. The extensive structural elaboration discovered compound22owhich possessed excellent IC50values of 0.06 and 0.23 μM against ALK-positive Karpas299 and H2228 cell lines, respectively. Meanwhile,22odisplayed encouraging inhibitory potency in the ALKWT(2.5 nM) and ALKL1196M(6.5 nM) enzymatic assays. Furthermore, the AO/EB and Hoechst 33258 assays illustrated22ocould induce cell apoptosis in a dose-dependent manner. Eventually, the molecular docking of22owith ALK clearly presented the vital interactions within the active site, which was in accordance with Type-I1/2inhibitor binding mode.