Drug Discovery And Mechanism Studies Of Small Molecule Inhibitors Of Indoleamine 2,3-dioxygenase

Indoleamine 2,3-dioxygenase 1(IDO1)is an intracellular monomeric heme-containing enzyme that catalyzes the first and rate liming step of L-tryptophan(L-Trp)catabolism via the kynurenine pathway.The reaction,that takes place through the oxidative cleavage of the tryptophan indole ring,is catalyzed by IDO1,indoleamine 2,3-dioxygenase 2(IDO2)and tryptophan 2,3-dioxygenase(TDO),independently in mammals.This reaction leads to a series of biologically actives metabolites,containing neurotransmitters serotonin?quinolinic acid?melatonin?N-methyl-D-aspartate(NMDA)receptor antagonist? kynurenic acid and finally the production of nicotinamide adenine dinucleotide(NAD).IDO1 inhibits the proliferation and differentiation of T cells through the catabolism of tryptophan,which are sensitive to the degradation of tryptophan and accumulation of tryptophan catabolites.Indeed,it had found that IDO1 overexpressed in many human cancer cells,such as breast?prostate?lung and colon cancers,acting as a direct guard against T-cell attack.Moreover,IDO1 is also found expressed within antigen presenting cells,which is to enhance peripheral tolerance to tumor associated antigens(TAAs)in tumor draining lymph nodes.By these mechanisms,IDO1 promotes the survival,invasion,growth and metastasis of malignant cells expressing TAAs by avoiding being recognition and attack by the immune system.Therefore,IDO1 inhibition is a potential therapeutic target for the cancer immunotherapy.In this study,DC-I028 which was discovered by protein structure-based and molecule docking-based virtual screening was identified as the hit compound of IDO1 inhibitor.According to the similarity searching and SMARTS searching,we purchased the derivatives of DC-I028 and tested the inhibition of IDO1 activity.Considering the structure-activity relationship(SAR)and putative binding modes,we deduced that DC-I028 was a novel scaffolds of potent IDO1 inhibitors.