1-(3,4-Diaminophenyl)-1H-pyrrole-2-carboxylic acids as potent apo-IDO1 inhibitors exhibiting efficacy in syngeneic tumor mouse models

Indolamine 2,3-dioxygenase 1 (IDO1)-mediated kynurenine pathway has been identified as an important immune escape mechanism in cancer, and pharmacological inhibition of IDO1 is regarded as a potential strategy for cancer treatment. Herein, we describe the identification of novel 1H-pyrrole-2-carboxylic acid-based IDO1 inhibitors targeting its apo form with picomolar potency in the HeLa cell-based assay. Among them, compound 45 showed the strongest inhibitory activity against IDO1 with an IC₅₀ value of 10 pM. Notably, oral administration of 45 at 10 mg/kg significantly suppressed tumor growth by activating antitumor immunity without significant toxicity in a CT26 syngeneic mouse model. Furthermore, the tumor burden could similarly be decreased in an LLC syngeneic mouse model treated with 45, indicating the potential of 45 for the treatment of distinct tumor types. Collectively, these data suggest that compound 45 may be used as a promising lead compound for further investigation.