Discovery of novel analogs of KHS101 as transforming acidic coiled coil containing protein 3 (TACC3) inhibitors for the treatment of glioblastoma.

Transforming acidic coiled coil containing protein 3 (TACC3) is emerging as an attractive anticancer target in recent years, however, few TACC3 small-molecular inhibitors have been reported up to now. In this study, fifteen compounds were designed and synthesized based on the lead compound KHS101 to find more potent TACC3 inhibitors. Among them, the most potent compound 7g exhibited about 10-folds more potent antiproliferative activities than KHS101 in various cancer cell lines. Two different protein-drug binding assays including DARTS, and CETSA revealed TACC3 as a biologically relevant target of compound 7g. In addition, compound 7g induced cell cycle arrest at the G2/M phase and induced cell apoptosis. Furthermore, compound 7g depolarized the MMP and induced ROS generation in a dose-dependent manner in U87 cells. More importantly, 7g reduced tumor weight by 72.7% in U87 xenograft model at a dose of 20 mg/kg/day without obvious toxicity. Altogether, compound 7g deserved further investigations as a novel, safe and efficacious TACC3 inhibitor for the treatment of GBM. [Display omitted] • Fifteen KHS101 analogs were designed and synthesized. • Compound 7g exhibited about 10-folds more potent antiproliferative activities than KHS101. • TACC3 was identified as a biologically relevant target of compound 7g. • 7g reduced tumor weight by 72.7% in U87 xenograft model without obvious toxicity. [ABSTRACT FROM AUTHOR]