Erianin

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.

Pancreatic cancer is a highly aggressive malignancy with poor prognosis and high mortality rates. KRAS mutations are ubiquitous in pancreatic cancer, driving tumorigenesis by promoting uncontrolled cell proliferation, survival, and metastasis. Therefore, identifying therapeutic agents effective against KRAS-mutant pancreatic cancer is urgently needed. Erianin, a benzyl compound isolated from Dendrobium candidum, exhibits potent cytotoxicity against KRAS-mutant pancreatic cancer cells (PANC-1: IC₅₀ ≈61.61 nM; MIA PaCa-2: IC₅₀ ≈54.37 nM), In contrast, it demonstrates minimal effects on KRAS wild-type BxPC-3 cells (>90 % viability at 1 μM). Despite its therapeutic potential, the molecular mechanisms underlying Erianin's anticancer effects remain poorly understood. Here, we demonstrated that Erianin significantly inhibits the proliferation and migration while inducing apoptosis in KRAS-mutations pancreatic cancer cells. Mechanistically, Erianin directly interacted with mitogen-activated protein kinase kinases 1 and 2 (MEK1/2), consequently suppressing the mitogen-activated protein kinase (MAPK) signaling pathway. In vivo, administration of Erianin (50 and 100 mg/kg) significantly inhibited tumor growth without observable toxicity in major organs using a Panc02 xenograft model. Additionally, Erianin disrupted pancreatic cancer stem cell properties, as evidenced by suppressed sphere-forming capacity and downregulated key stemness markers (CD133, CD44, SOX2, and OCT4). In conclusion, these findings demonstrate that Erianin directly interacts with MEK1/2, thereby inhibiting the activation of MAPK pathway and effectively suppressing both proliferation and stemness in pancreatic cancer cells. This work establishes Erianin as a promising candidate for the development of innovative anticancer therapeutics for pancreatic cancer, particularly KRAS mutations.