Discovery, synthesis and biological evaluation of novel isoquinoline derivatives as potent indoleamine 2, 3-dioxygenase 1 and tryptophan 2, 3-dioxygenase dual inhibitors.

Indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) play a pivotal role in regulating kynurenine catabolism pathway and immunosuppressive environment, which are promising drug targets for cancer immunotherapy. In this work, a variety of isoquinoline derivatives were designed, synthesized and evaluated for the inhibitory activity against IDO1 and TDO. The enzymatic assay and structure-activity relationship studies led to the most potent compound 43b with IC 50 values of 0.31 μM for IDO1 and 0.08 μM for TDO, respectively. Surface plasmon resonance (SPR) revealed direct binding affinity of compound 43b to IDO1 and TDO and molecular docking studies were performed to predict the possible binding mode. Further pharmacokinetic study and biological evaluation in vivo showed that 43b displayed acceptable pharmacokinetic profiles and potent antitumor efficacy with low toxicity in B16-F10 tumor model, which might provide some insights into the discovery of novel IDO1/TDO inhibitors for cancer immunotherapy.