Discovery of novel 1,2,3-triazole arylamide derivatives bearing dithiocarbamate moiety as dual inhibitors of tubulin and LSD1 with potent anticancer activity

Abstract

Targeted inhibition of tubulin polymerization or histone lysine-specific demethylase 1 (LSD1) is considered as a promising therapeutic strategy for cancer treatment. In this work, we reported the discovery of novel 1,2,3-triazole arylamide derivatives bearing dithiocarbamate moiety as dual tubulin polymerization and LSD1 inhibitors through the pharmacophore hybridization strategy, which were derived from the natural product Erianin, and evaluated their anticancer activity through in vitro assays. Among them, compound L-6 was identified as a potent dual tubulin polymerization and LSD1 inhibitor with effective anticancer potency, which demonstrated broad-spectrum antiproliferative activity in vitro with IC₅₀ values below 100 nM against 13 cancer cell lines. Notably, it displayed remarkable inhibitory potency on MGC-803 (IC₅₀ = 33 nM) and HGC-27 (IC₅₀ = 49 nM) gastric cancer cells, which surpassed those of Erianin and the LSD1 inhibitor ORY-1001. Mechanism explorations demonstrated that compound L-6 inhibited tubulin polymerization by targeting the colchicine binding site, thereby disrupting the microtubule network in gastric cancer cells. Additionally, it increased the methylation levels of H3K4me1/2 and H3K9me2/3 in a concentration-dependent manner, thus achieving epigenetic regulation. This dual mechanism involving microtubule depolymerization and epigenetic modulation enabled compound L-6 to effectively suppress colony formation, induce G2/M phase arrest, and promote apoptosis in gastric cancer cells, as well as regulate the expression levels of cell cycle and apoptosis-related proteins. These findings suggested that compound L-6, as a novel dual-target inhibitor of tubulin and LSD1, exhibited potential for the treatment of gastric cancer.