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

Graphical abstract Highlights • 38 Indazole derivatives were synthesized. • Compound 35 displayed the most IDO1 inhibitory potency. • Compound 35 was identified as an IDO1/TDO dual inhibitor. • Compound 35 decreased the INFγ-induced IDO1 expression. • Compound 35 exhibited in vivo antitumor activity in CT26 model. Abstract 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-1 H -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 IC 50 value of 0.74 μM in an enzymatic assay and 1.37 μM in HeLa cells. Quantitative analysis of the Western blot results indicated that 35 significantly decreased the INFγ-induced IDO1 expression in a concentration-dependent manner. In addition, 35 showed promising TDO inhibition with an IC 50 value of 2.93 μM in the enzymatic assay and 7.54 μM in A172 cells. Moreover, compound 35 exhibited in vivo antitumor activity in the CT26 xenograft model. These findings suggest that 1 H -indazole derivative 35 is a potent IDO1/TDO dual inhibitor, and has the potential to be developed for IDO1/TDO-related cancer treatment. [ABSTRACT FROM AUTHOR]