Design and Synthesis of Indoleamine 2,3-Dioxygenase 1 Inhibitors and Evaluation of Their Use as Anti-Tumor Agents

Abstract

Indoleamine 2,3-dioxygenase (IDO) 1 is the key enzyme for regulating tryptophan metabolism and is an important target for interrupting tumor immune escape. In this study, we designed four series of compounds as potential IDO1 inhibitors by attaching various fragments or ligands to indole or phenylimidazole scaffolds to improve binding to IDO1. The compounds were synthesized and their inhibitory activities against IDO1 and tryptophan 2,3-dioxygenase were evaluated. The cytotoxicities of the compounds against two tumor cell lines were also determined. Two compounds with a phenylimidazole scaffold (DX-03-12 and DX-03-13) showed potent IDO1 inhibition with IC50 values of 0.3–0.5 μM. These two IDO1 inhibitors showed low cell cytotoxicity, which indicated that they may exert their anti-tumor effect via immune modulation. Compound DX-03-12 was investigated further by determining the in vivo pharmacokinetic profile and anti-tumor efficacy. The pharmacokinetic study revealed that DX-03-12 had satisfactory properties in mice, with rapid absorption, moderate plasma clearance (∼36% of hepatic blood flow), acceptable half-life (∼4.6 h), and high oral bioavailability (∼96%). Daily oral administration of 60 mg/kg of compound DX-03-12 decreased tumor growth by 72.2% after 19 days in a mouse melanoma cell B16-F10 xenograft model compared with the untreated control. Moreover, there was no obvious weight loss in DX-03-12-treated mice. In conclusion, compound DX-03-12 is a potent lead compound for developing IDO1 inhibitors and anti-tumor agents.

Synthesis and evaluation of benzenesulfonic acid derivatives as human neutrophil elastase (hNE) inhibitors

“…They were cultured in DMEM medium (Invitrogen) with 10% fetal bovine serum (Gibco) at 37 °C with 5% CO 2 . All compounds were assessed the cyto-toxicity in five human cancer cell lines, namely HCT-116, HepG2, BGC-823, MCF-7, and A549 following the protocol of MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) cell proliferation assay [ 33 , 34 ].…”

Identification ACTA2 and KDR as key proteins for prognosis of PD‐1/PD‐L1 blockade therapy in melanoma

“…Statistical analysis was performed with GraphPad Prism 8.0 software and the significance level was evaluated with a one‐way ANOVA model. Studies involving mice were approved by the Experimental Animal Management and Welfare Committee at the Institute of Materia Medica, Peking Union Medical College 27‐31 …”

Identification ACTA2 and KDR as Key Proteins for Prognosis of PD-1/PD-L1 Blockade Therapy in Melanoma

“…Statistical analysis was performed with GraphPad Prism 8.0 software and the significance level was evaluated with a one-way ANOVA model. Studies involving mice were approved by the Experimental Animal Management and Welfare Committee at the Institute of Materia Medica, Peking Union Medical College [27][28][29][30][31].…”