Discovery of a novel potent tubulin inhibitor through virtual screening and target validation for cancer chemotherapy.

Abstract

Microtubules, critical to diverse cellular processes, represent a clinically validated target for anticancer therapeutics. In this study, a virtual screening of the Specs library, consisting of 200,340 compounds, was conducted to target the taxane and colchicine binding sites on tubulin, resulting in the identification of 93 promising candidates for further analysis. Subsequent characterization revealed a nicotinic acid derivative (compound 89) as a potent tubulin inhibitor, demonstrating significant anti-tumor efficacy in vitro and in vivo, with no observable toxicity at therapeutic doses in mice. Notably, compound 89 also exhibited robust antitumor activity in patient-derived organoids. Mechanistic studies, including EBI competitive binding assays and molecular docking, confirmed its inhibition toward tubulin polymerization via selective binding to the colchicine site. Furthermore, compound 89 disrupted tubulin assembly dynamics through modulation of the PI3K/Akt signaling pathway. This work presents a novel tubulin-inhibiting scaffold with potential for advancing next-generation microtubule-targeted chemotherapies.