Discovery of 2,4-diarylaminopyrimidine derivatives bearing dithiocarbamate moiety as novel ALK inhibitors

Abstract

To overcome drug resistance caused by ALK kinase mutations especially G1202R, two series of novel 2,4-diarylaminopyrimidine derivatives bearing dithiocarbamate moiety were designed, synthesized and evaluated for their biological activities. Among all the target compounds, B10 efficiently inhibited the proliferation of ALK-positive Karpas299 and H2228 cells both with IC₅₀ values of 0.07 μM. In addition, B10 exhibited remarkable enzymatic inhibitory potency with IC₅₀ values of 4.59 nM, 2.07 nM and 5.95 nM toward ALK^WT, ALK^L1196M and ALK^G1202R, respectively. Furthermore, B10 induced apoptosis in H2228 cell and caused cell cycle arrest in G2/M phase. Ultimately, the binding modes of B10 with ALK^WT and ALK^G1202R were ideally established, which further confirmed the structural basis in accordance with the SARs analysis. These results indicated that B10 was a potent ALK inhibitor for ALK^G1202R mutation treatment and deserved for further investigation.

Keywords: 2,4-Diarylaminopyrimidine; ALK; Anti-tumor evaluations; Dithiocarbamate; G1202R mutant; Synthesis.