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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-I ALK inhibitors.

著者 Miao X , Xing L , Guo M , Zhang H , Liu S , Yin S , Gong P , Zhang D , Zhai X
Bioorg Chem.2019 Nov 21 ; ():103456.
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Aiming to develop novel Type-I inhibitors of ALK to overcome extensive resistance mutations, especially the L1196M mutation surrounding the ATP pocket, two series of 2-arylaminopyrimidine derivatives (11a-f and 22a-t) were designed based on scaffold hopping. The extensive structural elaboration discovered compound 22o which possessed excellent IC values of 0.06 and 0.23 μM against ALK-positive Karpas299 and H2228 cell lines, respectively. Meanwhile, 22o displayed encouraging inhibitory potency in the ALK (2.5 nM) and ALK (6.5 nM) enzymatic assays. Furthermore, the AO/EB and Hoechst 33258 assays illustrated 22o could induce cell apoptosis in a dose-dependent manner. Eventually, the molecular docking of 22o with ALK clearly presented the vital interactions within the active site, which was in accordance with Type-I inhibitor binding mode.
PMID: 31787343 [PubMed - as supplied by publisher]
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