Discovery of Novel Imidazothiazole-Based Hydroxamic Acid Derivatives as Potent Indoleamine 2,3-Dioxygenase 1 and Histone Deacetylase 6 Dual Inhibitors

In order to take advantage of both immunotherapeutic and epigenetic antitumor agents, a series of imidazothiazole-based hydroxamic acid derivatives were designed based on the pharmacophore fusion strategy and evaluated as potent IDO1 and HDAC6 dual inhibitors. Among these inhibitors, the most potent compound <i>3-(4-Bromophenyl)-N-{4-[(7-(hydroxyamino)-7-oxoheptyl)amino]phenyl}imidazo[2,1-b]thiazole-5-carboxamide</i> (<b>10e</b>) showed considerable IDO1 inhibitory activity and a good selectivity profile for HDAC6 over the other HDAC isoforms. The intracellular inhibition of HDAC6 by <b>10e</b> was validated by Western blot analysis. Docking studies illustrated that the possible binding modes of compound <b>10e</b> interacted with IDO1 and HDAC6. Moreover, compound <b>10e</b> was found to arrest the cell cycle at the G2/M phase in HCT-116 cells. In particular, compound <b>10e</b> also exhibited potent in vivo antitumor efficacy in CT26 tumor-bearing BALB/c mice models, with no significant toxicity. Collectively, this work provides a promising lead compound that serves as IDO1/HDAC6 dual inhibitor for the development of novel antitumor agents.