N-Benzyl/Aryl Substituted Tryptanthrin as Dual Inhibitors of Indoleamine 2,3-Dioxygenase and Tryptophan 2,3-Dioxygenase

Abstract

Indoleamine 2,3-dioxygenase 1 (IDO1), which catalyzes the initial and rate-limiting step of the kynurenine pathway of tryptophan catabolism, has emerged as a key target in cancer immunotherapy because of its role in enabling cancers to evade the immune system. Tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase 2 (IDO2) catalyze the same reaction and play a potential role in cancer immunotherapy. Starting from our previously discovered tryptanthrin IDO1 inhibitor scaffold, we synthesized novel N-benzyl/aryl substituted tryptanthrin derivatives and evaluated their inhibitory efficacy on IDO1, TDO, and IDO2. Most compounds showed similar high inhibitory activities on both IDO1 and TDO, which were significantly superior over that of IDO2 with magnitude difference. We showed that N-benzyl/aryl substituted tryptanthrin directly interacted with IDO1, TDO, and IDO2, significantly augmented the proliferation of T cells in vitro, blocked the kynurenine pathway, and suppressed tumor growth when administered to LLC and H22 tumor-bearing mice.

AncPhore: A versatile tool for anchor pharmacophore steered drug discovery with applications in discovery of new inhibitors targeting metallo-β-lactamases and indoleamine/tryptophan 2,3-dioxygenases

“…These enzymes are first and rate-limiting enzymes of the kynurenine pathway, and implicated in neurodegenerative diseases and tumoral immune resistance; in particular, IDO1 and TDO have been demonstrated as important targets for cancer immunotherapy 23 , 24 , 25 , 26 . Although a number of IDO1 and TDO inhibitors have been reported and several inhibitors are in preclinical development 26 , 27 , 28 , 29 , discovery of new inhibitor chemotypes is still desirable at present. By comprehensive analysis of all reported complex structures for IDO1/TDO and the catalytic mechanisms of the tryptophan substrate ( Fig.…”

“…The human IDO1 (residues 12–403) and TDO (residues 19–388) 26 , 27 , 28 were cloned into pET28a vectors for expression with N-terminally His 6 -Tagged proteins. IDO1/TDO were overexpressed in E. coli Transetta (DE3) cells at 37 °C using LB medium supplied with 1 mmol/L 5-ALA and 30 μmol/L hemin chloride in a shaker at 200 rpm.…”

Discovery of a potent apo-IDO1 inhibitor for cancer immunotherapy

“…LPS stimulation of KP was performed in C57BL/6 mice as reported with some modifications (Yang et al, 2019). Briefly, Mice were injected i.p with Escherichia coli LPS (5 mg/kg) with a single oral dose of either the vehicle or B37 (10 mg/kg, ig) or EPA (50 mg/kg, ig), respectively.…”

Synthetic Tryptanthrin Derivatives Induce Cell Cycle Arrest and Apoptosis via Akt and MAPKs in Human Hepatocellular Carcinoma Cells

“…Multiple studies have shown that tryptanthrin suppresses tumor growth by modulating various targets, including p38, ERK, PIM1 kinase, and MDR1 [ 17 , 18 , 19 , 20 ]. Recent modifications of tryptanthrin have paved a way to obtain different targeted drugs that include amino-tryptanthrin derivatives such as topoisomerase II (Topo II), N -benzyl tryptanthrin derivatives such as indoleamine 2,3-dioxygenase (IDO), and tryptophan 2,3-dioxygenase (TDO) dual inhibitors ( Figure 1 A) [ 21 , 22 ]. In this study, we report the use of tryptanthrin as the lead compound to synthesize a series of tryptanthrin derivatives with improved anti-tumor activity.…”