Fragment-based discovery of novel phenyltriazolyl derivatives as allosteric type-I1/2 ALK inhibitors with promising antitumor effects

Based on the high-throughput screening hit BY-1, a series of phenyltriazolyl derivatives were developed. Satisfyingly, most compounds were detected moderate to excellent antitumor effects against Karpas299 and H2228 cells. Among them, 12k bearing 4‑hydroxypiperidinyl group exhibited the optimal activities against tested cells with IC₅₀ values of 51 nM and 175 nM, as well as promising inhibitory effects on ALK^WT (3.7 nM) and ALK^L1196M (6.8 nM). Unlike the conventional type-I ALK inhibitors, molecular models identified 12k as an allosteric type-I^1/2 inhibitor by forming key interactions in both the ATP binding region and the hydrophobic back pocket of ALK. Intriguingly, 12k could dose-dependently induce Apoptosis on H2228 cell and inhibit colony formation and tumor cell migration. Taken together, the rationalization of 12k may shed new light on the identification of novel allosteric type-I^1/2 ALK inhibitors.

Antitumor; Computational analysis; L1196M mutants; Phenyl-triazole; Type-I(1/2) ALK inhibitors.