Aiming to develop novel Type-I1/2 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 IC50 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 ALKWT (2.5 nM) and ALKL1196M (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-I1/2 inhibitor binding mode. READ ARTICLE
Bioorganic Chemistry DOI:10.1016/j.bioorg.2019.103456
Authors: Xiuqi Miao, Lingyun Xing, Ming Guo, Hong Zhang, Sicong Liu, Shiliang Yin, Ping Gong, Dajun Zhang, Xin Zhai
