4,6-Substituted-1 H-Indazoles as potent IDO1/TDO dual inhibitors

Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO) are constitutively overexpressed in many types of cancer cells and exert important immunosuppressive functions. In this article, a series of 4,6-substituted-1H-indazole derivatives were synthesized and evaluated the inhibitory activities against IDO1 and TDO, as well as their structure-activity relationships (SARs). Among these, compound 35 displayed the most IDO1 inhibitory potency with an IC50 value of 0.74 mu M in an enzymatic assay and 1.37 mu M in HeLa cells. Quantitative analysis of the Western blot results indicated that 35 significantly decreased the INF gamma-induced IDO1 expression in a concentration-dependent manner. In addition, 35 showed promising TDO inhibition with an IC50 value of 2.93 mu M in the enzymatic assay and 7.54 mu M in A172 cells. Moreover, compound 35 exhibited in vivo antitumor activity in the CT26 xenograft model. These findings suggest that 1H-indazole derivative 35 is a potent IDO1/TDO dual inhibitor, and has the potential to be developed for IDO1/TDO-related cancer treatment.