Discovery of novel thienopyridine indole derivatives as inhibitors of tubulin polymerization targeting the colchicine-binding site with potent anticancer activities

Based on the molecular hybridization strategy, novel thienopyridine indole derivatives were designed and synthesized as tubulin polymerization inhibitors, and the in vitro antiproliferative potency on MGC-803, KYSE450 and HCT-116 cells was evaluated. Among them, compound 20b showed a broad-spectrum antiproliferative activity against 11 Cancer cell lines, with IC₅₀ values below 4 nmol/L. Notably, it demonstrated exceptional efficacy against MGC-803 (IC₅₀ = 1.61 nmol/L) and HGC-27 (IC₅₀ = 1.82 nmol/L) cells. Further mechanism explorations suggested that compound 20b could inhibit tubulin polymerization (IC₅₀ = 2.505 μmol/L) by acting on the colchicine binding site, thereby disrupting intracellular microtubule networks and interfering with cell mitosis. In addition, compound 20b effectively inhibited the colony formation and cell migration activities, and induced G2/M phase cycle arrest and Apoptosis in MGC-803 and HGC-27 cells. Besides, compound 20b also displayed potent anti-angiogenesis effects on HUVECs. Importantly, compound 20b demonstrated oral efficacy in inhibiting tumor growth with a TGI of 45.8 % (5 mg/kg/qod) in the mouse xenograft model bearing MGC-803 cells, surpassing that of CA-4 (TGI of 27.1 % at 20 mg/kg/qod), as well as also exhibited a good safety profile. Therefore, these results suggested that the thienopyridine indole derivative 20b represents a novel tubulin inhibitor with potent Anticancer efficacy that inhibits gastric cancers.

Antiproliferative activities; Colchicine-binding site; Indole; Thienopyridine; Tubulin.