Screening Of Novel Highly Effective IDO Inhibitors And Its Role In Cancer Treatment

Indoleamine2,3-dioxygenase (IDO) is the first and rate-limiting enzyme in the kynurenine pathway of tryptophan catabolism ultimately leads to the production of the L-kynurenine and quinolinic acid (QUIN). IDO is emerging as an important new therapeutic target for the treatment of cancer, neurological disorders and other diseases that are characterized by pathological tryptophan metabolism. IDO inhibition is proposed to have therapeutic potential. However, only a few structural classes are known to be IDO inhibitors. In this study, a natural compound CX was discovered to be a novel potent IDO-1inhibitor by the enzyme assay. A series of CX derivatives were later synthesized. The IDO inhibition activity of CX derivatives was investigated, and enzyme kinetics constants were determined. As a result, thirteen CX derivatives are potent IDO-1inhibitors with higher activity than that of1-MT, which is the commonly used IDO inhibitor. Besides, testing in a human HEK293cell line provided further evidence that CX derivatives were potent inhibitors of IDO. It was exciting to find that three CX derivatives exhibited IDO inhibitory activity at a nanomolar level. After that, molecular docking studies were performed and the binding modes of CX derivatives to the human IDO-1were determined. In addition, CX derivatives dramatically augmented the proliferation of T cells in mixed lymphocyte reaction system. To investigate whether CX derivatives as IDO inhibitiors could similarly reverse immune tolerance in vivo, we treated mice bearing LLC with an IDO-1inhibitor (CX-47or1-MT). The results found that CX-47significantly suppressed tumor growth and inhibited IDO activity. In addition, CX-47reduced the numbers of Foxp3+regulatory T cells (Tregs), which are known to prevent the development of efficient antitumor immune responses by intercellular contacts and inhibitory cytokines. Taken together, these results lead us to propose that CX-47is an attractive small molecule IDO-1inhibitor that may be used as an antitumor agent.