Discovery of a Novel Hybrid of Vorinostat and Riluzole as a Potent Antitumor Agent

Vorinostat (suberoylanilide hydroxamic acid) was the first approved histone deacetylase (HDAC) inhibitor in a group of validated cancer therapeutic agents targeting epigenetics. Riluzole is a drug used to treat amyotrophic lateral sclerosis, the antitumor potency of which has been recently revealed. Herein, a novel hybrid of vorinostat and riluzole (compound1) was rationally designed, synthesized, and evaluated. Compared with vorinostat, compound1exhibited superior total HDAC inhibitory activity and similar HDAC isoform selective profiles. The intracellular HDAC inhibition of compound1was confirmed by Western blot analysis. Moreover, compound1possessed more potentin vitroantiproliferative activity against all tested solid and hematological tumor cell lines than vorinostat.In vitrometabolic stability evaluation of compound1revealed better human plasma stability and comparable human liver microsomal stability than vorinostat. Additionally, compound1demonstrated more significantin vivoantitumor activity in a MDA-MB-231 xenograft model than vorinostat, which could be attributed to its superiorin vitroantiproliferative activity and metabolic stability. Taken together, the results presented here support further research and development of compound1as a promising antitumor agent.