Identification of highly potent 2,4‐diarylaminopyrimidine analogs of a typical piperidinyl‐4‐ol moiety as promising antitumor ALK inhibitors

Abstract In light of the cocrystal structure of ceritinib with anaplastic lymphoma kinase (ALK) WT protein, a series of novel 2,4‐diarylaminopyrimidine analogs ( L1 – L25 ) bearing a typical piperidinyl‐4‐ol moiety were designed and synthesized with improved biological and physicochemical properties. Satisfyingly, most compounds demonstrated moderate to excellent antitumor effects with IC 50 values below 5 μM on ALK‐positive Karpas299 and H2228 cells. In particular, L6 bearing the 1‐(6‐methoxy‐pyridin‐2‐yl)‐4‐(morpholinomethyl)piperidinyl‐4‐ol moiety was detected as the optimal compound against ALK‐dependent cell lines of Karpas299 (0.017 μM) and H2228 cells (0.052 μM), in company with encouraging ALK enzyme inhibition (ALK WT , IC 50 = 1.8 nM). In addition, L6 was also capable of inhibiting ALK‐resistant mutations, including ALK L1196M (3.9 nM) and ALK G1202R (5.2 nM). Remarkably, L6 typically repressed colony formation and migration of H2228 cells in a dose‐dependent manner. Meanwhile, acridine orange‐ethidium bromide staining analysis indicated that the proapoptotic effect of L6 was better than that of ceritinib at the same concentration (50 nM). Ultimately, the binding patterns of L6 to ALK WT and ALK G1202R were ideally established, which further confirmed the structural basis in accordance with the structure–activity relationship analysis.