A series of hybrid anaplastic lymphoma kinase (ALK) inhibitors (Y1∼Y30) were designed by assembling aminoindazole of Entrectinib onto 2-position of 2,4-diarylaminopyrimidine (DAAP) fragment to serve as ATP dual-mimic agents. Under structure-based optimization, all conjugates were detected moderate to excellent cytotoxicity potency, among which the pyrrolidine analog Y28 exerted optimal antiproliferative effects on ALK-addicted cell lines with IC50 values below 20 nM. As a highly potent ALK inhibitor (ALKWT, IC50 = 1.6 nM), Y28 was also capable of suppressing ALK-resistant mutations including ALKL1196M (0.71 nM) and ALKG1202R (1.3 nM). Intriguingly, Y28 turned out to effectively inhibit colony formation and restrain cell migration of H2228 cells in a dose dependent manner. In addition, flow cytometric analysis indicated that Y28 could induce cell apoptosis and achieve cell cycle arrest in G2 phase. Notably, oral administration of Y28 at 50 mg/kg regressed tumor in the H2228 xenograft model with tumor growth inhibition value of 70.46%. Finally, the binding models of Y28 with ALKWT & ALKG1202R within the active site well established its mode of action and accounted for the superior activities as a promising antitumor candidate.
Keywords: ALK; ATP dual-Mimic; Antitumor evaluation; Hybrid modification; Synthesis.
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