Inhibitory effects of flavonoids isolated from Sophora flavescens on indoleamine 2,3-dioxygenase 1 activity
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
Authors: Kwon, Mincheol; Ko, Sung-Kyun; Jang, Mina; Kim, Gun-Hee; Ryoo, In-Ja; Son, Sangkeun; Ryu, Hyung Won; Oh, Sei-Ryang; Lee, Won-Kyu; Kim, Bo Yeon; Jang, Jae-Hyuk; Ahn, Jong Seog
Abstract
Indoleamine 2,3-dioxygenase 1 (IDO1), a tryptophan catabolising enzyme, is known as a tumour cell survival factor that causes immune escape in several types of cancer. Flavonoids of Sophora flavescens have a variety of biological benefits for humans; however, cancer immunotherapy effect has not been fully investigated. The flavonoids (1-6) isolated from S. flavescens showed IDO1 inhibitory activities (IC50 4.3-31.4 mu M). The representative flavonoids (4-6) of S. flavescens were determined to be non-competitive inhibitors of IDO1 by kinetic analyses. Their binding affinity to IDO1 was confirmed using thermal stability and surface plasmon resonance (SPR) assays. The molecular docking analysis and mutagenesis assay revealed the structural details of the interactions between the flavonoids (1-6) and IDO1. These results suggest that the flavonoids (1-6) of S. flavescens, especially kushenol E (6), as IDO1 inhibitors might be useful in the development of immunotherapeutic agents against cancers.
Design, Synthesis and Biological Evaluation of Novel 1,2,5-Oxadiazol-3-Carboximidamide Derivatives as Indoleamine 2, 3-Dioxygenase 1 (IDO1) Inhibitors
ANTI-CANCER AGENTS IN MEDICINAL CHEMISTRY
Authors: Xia, Zhifeng; Nan, Yanyang; Liu, Chang; Lin, Guangyu; Gu, Kedan; Chen, Cheng; Zhao, Weili; Ju, Dianwen; Dong, Xiaochun
Abstract
Background and Objective: Indoleamine-2,3-dioxygenase 1 (IDO1), which catalyzes the degradation of L-tryptophan (L-Trp) to N-formyl kynurenine (NFK) in the first and rate-limiting step of Kynurenine (KYN) pathway has been identified as a promising therapeutic target for cancer immunotherapy. The small molecule Epacadostat developed by incyte Corp is the most advanced IDO1 inhibitor in clinical trials. Methods: In this study, various amidine derivatives were individually installed as the polar capping group onto the amino ethylene side chain to replace the sulfamoylamino moiety of Epacadostat to develop novel IDO1 inhibitors. A series of novel 1,2,5-oxadiazol-3-carboximidamide derivatives were designed, prepared, and evaluated for their inhibitory activities against human IDO1 enzyme and cellular IDO1. Results: In vitro human IDO1 enzyme and cellular IDO1 assay results demonstrate that the inhibitory activities of compound 13a and 13b were comparable to Epacadostat, with the enzymatic IC50 values of 49.37nM and 52.12nM and cellular IC50 values of 12.34nM and 14.34nM, respectively. The anti-tumor efficacy of 13b is slightly better than Epacadosta in Lewis Lung Cancer (LLC) tumor-bearing mice model. Conclusion: 13b is a potent IDO1 inhibitor with therapeutic potential in tumor immunotherapy.