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 (compound ) was rationally designed, synthesized, and evaluated. Compared with vorinostat, compound exhibited superior total HDAC inhibitory activity and similar HDAC isoform selective profiles. The intracellular HDAC inhibition of compound was confirmed by Western blot analysis. Moreover, compound possessed more potent antiproliferative activity against all tested solid and hematological tumor cell lines than vorinostat. metabolic stability evaluation of compound revealed better human plasma stability and comparable human liver microsomal stability than vorinostat. Additionally, compound demonstrated more significant antitumor activity in a MDA-MB-231 xenograft model than vorinostat, which could be attributed to its superior antiproliferative activity and metabolic stability. Taken together, the results presented here support further research and development of compound as a promising antitumor agent.