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

## TL;DR

Scientists designed a new compound that can inhibit two cancer-related enzymes, showing strong antitumor effects in mice without significant toxicity.

## Contribution

A novel imidazothiazole-based hydroxamic acid derivative was developed as a dual inhibitor of IDO1 and HDAC6 with potent antitumor activity.

## Key findings

- Compound 10e exhibited strong IDO1 inhibition and selectivity for HDAC6 over other isoforms.
- Compound 10e arrested the cell cycle at the G2/M phase in HCT-116 cells.
- Compound 10e showed potent in vivo antitumor efficacy in a mouse model without significant toxicity.

## Abstract

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 3-(4-Bromophenyl)-N-{4-[(7-(hydroxyamino)-7-oxoheptyl)amino]phenyl}imidazo[2,1-b]thiazole-5-carboxamide (10e) showed considerable IDO1 inhibitory activity and a good selectivity profile for HDAC6 over the other HDAC isoforms. The intracellular inhibition of HDAC6 by 10e was validated by Western blot analysis. Docking studies illustrated that the possible binding modes of compound 10e interacted with IDO1 and HDAC6. Moreover, compound 10e was found to arrest the cell cycle at the G2/M phase in HCT-116 cells. In particular, compound 10e 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.