Journal: Cell

Article Title: Dietary and Microbial Oxazoles Induce Intestinal Inflammation by Modulating Aryl Hydrocarbon Receptor Responses

doi: 10.1016/j.cell.2018.04.037

Figure Lengend Snippet: (A) Recombinant IDO1 was incubated with L-tryptophan in the presence of oxazole (oxazolone, TMO, Frag-oz), control (TMC) compounds, or vehicle and formyl-kynurenine production measured via calorimetric assay. ***p < 0.001 (Student’s t test)

Article Snippet: IDO1 Inhibitor Screening Assay Kit , BPS Biosciences , Cat# 72021.

Techniques: Recombinant, Incubation

Journal: Cell

Article Title: Dietary and Microbial Oxazoles Induce Intestinal Inflammation by Modulating Aryl Hydrocarbon Receptor Responses

doi: 10.1016/j.cell.2018.04.037

Figure Lengend Snippet: IECs promote mucosal barrier protection through microsomal triglyceride protein (MTP)-mediated CD1d-restricted production of IL-10 (blue circles). Upon exposure to oxazole compounds (derived from diet, microbes, or other environmental sources), these CD1d-restricted responses are attenuated through a mechanism involving the production of tryptophan-derived metab-olites (kynurenic acid, xanthurenic acid; orange squares) through the activity of IDO1 that trigger the AhR. Decreased, CD1d-restricted IL-10 production results in unrestrained inflammatory responses (IL-13/IFNγ, red dots) and resulting pathology. ER, endoplasmic reticulum.

Article Snippet: IDO1 Inhibitor Screening Assay Kit , BPS Biosciences , Cat# 72021.

Techniques: Derivative Assay, Activity Assay

Journal: Cell

Article Title: Dietary and Microbial Oxazoles Induce Intestinal Inflammation by Modulating Aryl Hydrocarbon Receptor Responses

doi: 10.1016/j.cell.2018.04.037

Figure Lengend Snippet: KEY RESOURCES TABLE

Article Snippet: IDO1 Inhibitor Screening Assay Kit , BPS Biosciences , Cat# 72021.

Techniques: Recombinant, Enzyme-linked Immunosorbent Assay, Screening Assay, Luciferase, SYBR Green Assay, Software, Microscopy, Mass Spectrometry

Journal: MedChemComm

Article Title: Advances in indoleamine 2,3-dioxygenase 1 medicinal chemistry

doi: 10.1039/c7md00109f

Figure Lengend Snippet: The chemical structures of the substrate ( 1 ) and product ( 2 ) of the rate limiting step of the kynurenine pathway are shown in the dashed box. The chemical structures of drug candidates targeting IDO1 ( 3–6 ) are shown outside of the box. The structures of compounds 5 and 6 are undisclosed.

Article Snippet: More recently, a novel IDO1 inhibitor (PF-06840003, 5 , ), developed by researchers at iTeos Therapeutics and licensed to Pfizer, has entered phase I clinical trials for the treatment of patients with malignant gliomas.

Techniques:

Journal: MedChemComm

Article Title: Advances in indoleamine 2,3-dioxygenase 1 medicinal chemistry

doi: 10.1039/c7md00109f

Figure Lengend Snippet: Structure of IDO1 and structure–function relationships depicting residues involved in holding the heme group (box A), ITIM mediated signaling functions (box B), and catalytic activity (box C).

Article Snippet: More recently, a novel IDO1 inhibitor (PF-06840003, 5 , ), developed by researchers at iTeos Therapeutics and licensed to Pfizer, has entered phase I clinical trials for the treatment of patients with malignant gliomas.

Techniques: Activity Assay

Journal: MedChemComm

Article Title: Advances in indoleamine 2,3-dioxygenase 1 medicinal chemistry

doi: 10.1039/c7md00109f

Figure Lengend Snippet: (A) The catalytic cleft of IDO1 is shaped with two pockets: pocket A (yellow surface) is mostly composed of aromatic and hydrophobic residues, while pocket B (magenta surface) is made of one positively charged residue and aromatic residues. (B) Co-crystallized inhibitors ( 14 , 19–21 ) with shadow colors indicating the part of the chemical structure occupying pocket A (yellow) and/or pocket B (magenta).

Article Snippet: More recently, a novel IDO1 inhibitor (PF-06840003, 5 , ), developed by researchers at iTeos Therapeutics and licensed to Pfizer, has entered phase I clinical trials for the treatment of patients with malignant gliomas.

Techniques: Residue

Journal: MedChemComm

Article Title: Advances in indoleamine 2,3-dioxygenase 1 medicinal chemistry

doi: 10.1039/c7md00109f

Figure Lengend Snippet: Proposed binding mode of epacadostat ( 4 ) to IDO1 as a result of the docking study reported in . Intra-molecular hydrogen bonds of 4 are shown with dashed black lines.

Article Snippet: More recently, a novel IDO1 inhibitor (PF-06840003, 5 , ), developed by researchers at iTeos Therapeutics and licensed to Pfizer, has entered phase I clinical trials for the treatment of patients with malignant gliomas.

Techniques: Binding Assay

Journal: MedChemComm

Article Title: Advances in indoleamine 2,3-dioxygenase 1 medicinal chemistry

doi: 10.1039/c7md00109f

Figure Lengend Snippet: Binding mode of 4-PI ( 14 , shown in green carbon atom sticks) to IDO1 resulting from crystallographic studies (pdb code: ; 2D0T ). Key residues for structure–activity relationships are labeled and shown in yellow carbon atom sticks. CHES ( 15 ) molecules binding to the catalytic cleft are also shown in green carbon atom sticks.

Article Snippet: More recently, a novel IDO1 inhibitor (PF-06840003, 5 , ), developed by researchers at iTeos Therapeutics and licensed to Pfizer, has entered phase I clinical trials for the treatment of patients with malignant gliomas.

Techniques: Binding Assay, Activity Assay, Labeling

Journal: MedChemComm

Article Title: Advances in indoleamine 2,3-dioxygenase 1 medicinal chemistry

doi: 10.1039/c7md00109f

Figure Lengend Snippet: Binding mode of the NLG919 analogue ( 19 , shown in green carbon atom sticks) to IDO1 resulting from crystallographic studies (pdb code: ; 5EK3 ). Key residues are labeled and shown in yellow carbon atom sticks. Inter- and intra-molecular hydrogen bonds of 19 are shown with dashed black lines.

Article Snippet: More recently, a novel IDO1 inhibitor (PF-06840003, 5 , ), developed by researchers at iTeos Therapeutics and licensed to Pfizer, has entered phase I clinical trials for the treatment of patients with malignant gliomas.

Techniques: Binding Assay, Labeling

Journal: MedChemComm

Article Title: Advances in indoleamine 2,3-dioxygenase 1 medicinal chemistry

doi: 10.1039/c7md00109f

Figure Lengend Snippet: Chemical structures of IDO1 inhibitors ( 20–25 ) with a hypothetical non-competitive and/or uncompetitive mechanism of inhibition.

Article Snippet: More recently, a novel IDO1 inhibitor (PF-06840003, 5 , ), developed by researchers at iTeos Therapeutics and licensed to Pfizer, has entered phase I clinical trials for the treatment of patients with malignant gliomas.

Techniques: Inhibition

Journal: MedChemComm

Article Title: Advances in indoleamine 2,3-dioxygenase 1 medicinal chemistry

doi: 10.1039/c7md00109f

Figure Lengend Snippet: Binding mode of imidazothiazole derivative 21 (shown in green carbon atom sticks) to IDO1 resulting from crystallographic studies (pdb code: ; 4PK6 ). Phe226 and Arg231 are labeled and shown in sticks. Ligand-induced conformational changes are highlighted with dashed arrows from positions observed in the Amg-1 ( 20 ) bound crystal structure of IDO1 (Phe226 and Arg231 shown in yellow atom sticks, pdb code: ; 4PK6 ) to actual positions in the ligand 21 bound complex (Phe226 and Arg231 shown in green atom sticks, pdb code: ; 4PK5 ).

Article Snippet: More recently, a novel IDO1 inhibitor (PF-06840003, 5 , ), developed by researchers at iTeos Therapeutics and licensed to Pfizer, has entered phase I clinical trials for the treatment of patients with malignant gliomas.

Techniques: Binding Assay, Labeling

Journal: Frontiers in Pharmacology

Article Title: Discovery of Novel Inhibitors of Indoleamine 2,3-Dioxygenase 1 Through Structure-Based Virtual Screening

doi: 10.3389/fphar.2018.00277

Figure Lengend Snippet: Several published IDO1 inhibitors.

Article Snippet: Another small molecule IDO1 inhibitor INCB024360 (also named as epacadostat) developed by Incyte, Inc., shows potent inhibitory activity against IDO1 (Yue et al., ).

Techniques:

Journal: Frontiers in Pharmacology

Article Title: Discovery of Novel Inhibitors of Indoleamine 2,3-Dioxygenase 1 Through Structure-Based Virtual Screening

doi: 10.3389/fphar.2018.00277

Figure Lengend Snippet: A novel IDO1 inhibitor, DCI-028, was discovered by a virtual screening model based on the 3D structure of the target. Further hit expansion work brought a more potent molecule, DCI-02806.

Article Snippet: Another small molecule IDO1 inhibitor INCB024360 (also named as epacadostat) developed by Incyte, Inc., shows potent inhibitory activity against IDO1 (Yue et al., ).

Techniques:

Journal: Frontiers in Pharmacology

Article Title: Discovery of Novel Inhibitors of Indoleamine 2,3-Dioxygenase 1 Through Structure-Based Virtual Screening

doi: 10.3389/fphar.2018.00277

Figure Lengend Snippet: Virtual screening procedures and activity assays for IDO1 in vitro . (A) Flowchart of the integrated virtual screening for IDO1 inhibitors. Numeral indicates the number of molecules in each stage. (B) Inhibitory activity of the 104 candidate molecules at 50 μM. The red columnar bars represent the inhibitory activity of compounds against IDO1. NLG919 was the reference compound. (C) The inhibitory activity of DC-I028 against IDO1 at enzymatic level. (D) The IDO1 inhibitory activity of DC-I028 in Hela cells.

Article Snippet: Another small molecule IDO1 inhibitor INCB024360 (also named as epacadostat) developed by Incyte, Inc., shows potent inhibitory activity against IDO1 (Yue et al., ).

Techniques: Activity Assay, In Vitro

Journal: Frontiers in Pharmacology

Article Title: Discovery of Novel Inhibitors of Indoleamine 2,3-Dioxygenase 1 Through Structure-Based Virtual Screening

doi: 10.3389/fphar.2018.00277

Figure Lengend Snippet: Inhibition ratio data of six candidate hits of virtual screening, as measured by the Absorbance 321 assay on IDO1.

Article Snippet: Another small molecule IDO1 inhibitor INCB024360 (also named as epacadostat) developed by Incyte, Inc., shows potent inhibitory activity against IDO1 (Yue et al., ).

Techniques: Inhibition

Journal: Frontiers in Pharmacology

Article Title: Discovery of Novel Inhibitors of Indoleamine 2,3-Dioxygenase 1 Through Structure-Based Virtual Screening

doi: 10.3389/fphar.2018.00277

Figure Lengend Snippet: Comparison of the binding modes of 4-PI (magenta) and DC-I028 (orange) in the active site of IDO1 (PDB ID: 4U74). Interactions with metal were shown as dashed lines. Key residues for ligand binding are shown as sticks. The surface of the pocket was shown as wireframes. The figure depicting the binding modes was generated with PyMOL (Schrodinger, ).

Article Snippet: Another small molecule IDO1 inhibitor INCB024360 (also named as epacadostat) developed by Incyte, Inc., shows potent inhibitory activity against IDO1 (Yue et al., ).

Techniques: Comparison, Binding Assay, Ligand Binding Assay, Generated

Journal: Frontiers in Pharmacology

Article Title: Discovery of Novel Inhibitors of Indoleamine 2,3-Dioxygenase 1 Through Structure-Based Virtual Screening

doi: 10.3389/fphar.2018.00277

Figure Lengend Snippet: Comparison of the binding modes of DC-I028 (orange) and DC-I02806 (cyan) in the active site of IDO1 (PDB ID: 4U74). Metal and hydrogen bonding interactions were shown as red dashed lines. Key residues for ligand binding are shown as sticks. The surface of the pocket was shown as wireframes. The figure depicting the binding modes was generated with PyMOL (Schrodinger, ).

Article Snippet: Another small molecule IDO1 inhibitor INCB024360 (also named as epacadostat) developed by Incyte, Inc., shows potent inhibitory activity against IDO1 (Yue et al., ).

Techniques: Comparison, Binding Assay, Ligand Binding Assay, Generated

Journal: Frontiers in Pharmacology

Article Title: Discovery of Novel Inhibitors of Indoleamine 2,3-Dioxygenase 1 Through Structure-Based Virtual Screening

doi: 10.3389/fphar.2018.00277

Figure Lengend Snippet: Inhibition of IDO1 activity by analogs of DC-I028.

Article Snippet: Another small molecule IDO1 inhibitor INCB024360 (also named as epacadostat) developed by Incyte, Inc., shows potent inhibitory activity against IDO1 (Yue et al., ).

Techniques: Inhibition, Activity Assay

Journal: PLoS ONE

Article Title: Inhibition of immune checkpoints PD-1, CTLA-4, and IDO1 coordinately induces immune-mediated liver injury in mice

doi: 10.1371/journal.pone.0217276

Figure Lengend Snippet: Pharmacokinetics (PK)/pharmacodynamics (PD) in (A) wild-type and (B) PD-1 -/- mice. Mice were administered epacadostat at doses of 100, 300, and 600 mg/kg/dose by oral gavage at t = 0 h and t = 6 h, and total plasma concentrations of epacadostat and kynurenine were measured by LC-MS/MS. Epacadostat concentrations were below the limit of quantification at 24 h for the 100 mg/kg BID dose. All values are reported as mean ± SD. n = 3 (WT) and 3 ( PD-1 -/- ). PD: pharmacodynamics, PK: pharmacokinetics, BID: bis in die (twice daily).

Article Snippet: The IDO1 inhibitor epacadostat (Chemscene, Monmouth Junction, NJ) was administered twice daily (6 hours between each dose) as an oral gavage formulation with 0.5% HPMC/0.25% Tween 20 in a water base at 100, 300 or 600 mg/kg/dose.

Techniques: Drug discovery, Clinical Proteomics, Liquid Chromatography with Mass Spectroscopy

Journal: PLoS ONE

Article Title: Inhibition of immune checkpoints PD-1, CTLA-4, and IDO1 coordinately induces immune-mediated liver injury in mice

doi: 10.1371/journal.pone.0217276

Figure Lengend Snippet: Mice were treated with 300 mg/kg BID epacadostat and/or 9D9 for 4 weeks (see methods). (A) Representative H&E images and quantification of liver (B) single cell necrosis and (C) periportal infiltration. (D) GLDH. (E) Quantification of T cells by flow cytometry. Necrosis, infiltration and GLDH data were analyzed with a Kruskal-Wallis test and Dunn’s multiple comparisons test. Flow cytometry data was analyzed with an ordinary one-way ANOVA with Tukey’s multiple comparisons test. Arrows indicate immune cell accumulation. Arrowheads indicate a necrotic cell. Scale bar = 150 μm. All data are reported as mean ± SEM *P<0.05, ***P<0.001, n = 6 per group. GLDH: glutamate dehydrogenase.

Article Snippet: The IDO1 inhibitor epacadostat (Chemscene, Monmouth Junction, NJ) was administered twice daily (6 hours between each dose) as an oral gavage formulation with 0.5% HPMC/0.25% Tween 20 in a water base at 100, 300 or 600 mg/kg/dose.

Techniques: Flow Cytometry

Journal: PLoS ONE

Article Title: Inhibition of immune checkpoints PD-1, CTLA-4, and IDO1 coordinately induces immune-mediated liver injury in mice

doi: 10.1371/journal.pone.0217276

Figure Lengend Snippet: PD-1 -/- mice were treated with 9D9, epacadostat (A, C panels are 300 mg/kg BID only, B includes 300 and 600 mg/kg BID), or in combination for 2 or 6 weeks. (A) Representative H&E images and (B) quantification of single cell necrosis. (C) GLDH levels through 6 weeks. Arrows indicate immune cell accumulation. Arrowheads indicate a necrotic cell. Scale bar = 150 μm. All data (n = 6 per group) are reported as mean ± SEM. Necrosis data was analyzed with a Kruskal-Wallis test and Dunn’s multiple comparisons test. GLDH data was analyzed with a repeated measures two-way ANOVA and Tukey’s multiple comparisons test. a P < 0.05 9D9 + epacadostat vs vehicle, 9D9, b P < 0.05 9D9 + epacadostat vs epacadostat, c P < 0.05 epacadostat vs vehicle, 9D9.

Article Snippet: The IDO1 inhibitor epacadostat (Chemscene, Monmouth Junction, NJ) was administered twice daily (6 hours between each dose) as an oral gavage formulation with 0.5% HPMC/0.25% Tween 20 in a water base at 100, 300 or 600 mg/kg/dose.

Techniques:

Journal: PLoS ONE

Article Title: Inhibition of immune checkpoints PD-1, CTLA-4, and IDO1 coordinately induces immune-mediated liver injury in mice

doi: 10.1371/journal.pone.0217276

Figure Lengend Snippet: PD-1 -/- mice were treated with 9D9, lower dose (300 mg/kg BID) epacadostat or in combination for 2 or 6 weeks. (A) Representative images of the mid-zonal/centrilobular region of the liver in the vehicle and combination groups. Semi-quantitative analysis of immunohistochemical detection of CD4, CD8α or Foxp3 at (B) 2 and (C) 6 weeks of treatment. (D) Statistical measure of the strength of association (gamma value) between liver hepatocyte necrosis score with GLDH, immune infiltrates, and immunohistochemistry scores. All data (n = 6 per group) are reported as mean ± SEM. Immune cell scores were analyzed with a Kruskal-Wallis test and Dunn’s multiple comparisons test. Scale bar = 300 μm. *P<0.05, **P<0.01, ***P<0.0001. p: periportal, mc: mid-zonal/centrilobular.

Article Snippet: The IDO1 inhibitor epacadostat (Chemscene, Monmouth Junction, NJ) was administered twice daily (6 hours between each dose) as an oral gavage formulation with 0.5% HPMC/0.25% Tween 20 in a water base at 100, 300 or 600 mg/kg/dose.

Techniques: Immunohistochemical staining, Immunohistochemistry

Journal: PLoS ONE

Article Title: Inhibition of immune checkpoints PD-1, CTLA-4, and IDO1 coordinately induces immune-mediated liver injury in mice

doi: 10.1371/journal.pone.0217276

Figure Lengend Snippet: Mice were treated with anti-mouse CTLA-4 (9D9), lower dose (300 mg/kg BID) epacadostat or in combination for 6 weeks (A–H) or 3 weeks (I). Single cell suspensions of the whole liver were analyzed for (A) CD45+ cells, (B) CD11b+F4/80+ macrophages, (C) Gr1+CD11b+ myeloid derived suppressor cells (MDSC)s, (D) CD49b+ natural kill (NK) cells, (E) CD3+ T cells, (F) CD3+CD8+ T cells (G) CD3+CD4+ T cells, (H) Foxp3+CD4+ T cells, and (I) Ki67+ T cell subsets by flow cytometry. All data are reported as mean ± SEM. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001, n = 6 per group, one-way ANOVA with Tukey’s multiple comparisons test (A–H) or n = 12 per group, unpaired t-test (I).

Article Snippet: The IDO1 inhibitor epacadostat (Chemscene, Monmouth Junction, NJ) was administered twice daily (6 hours between each dose) as an oral gavage formulation with 0.5% HPMC/0.25% Tween 20 in a water base at 100, 300 or 600 mg/kg/dose.

Techniques: Derivative Assay, Flow Cytometry

Journal: PLoS ONE

Article Title: Inhibition of immune checkpoints PD-1, CTLA-4, and IDO1 coordinately induces immune-mediated liver injury in mice

doi: 10.1371/journal.pone.0217276

Figure Lengend Snippet: Mice were treated with anti-mouse CTLA-4 (9D9), 300 mg/kg BID epacadostat or in combination for 6 weeks (A-E) or with 600 mg/kg BID epacadostat or in combination for 2 weeks (F-G). Linear regression analysis of (A) leukocytes (CD45+ cells), (B) macrophages, (C) total T cells and (D) CD4+ and (E) CD8+ T cells as defined in with single cell necrosis. (F) The top activated (> 1.5 z-score) toxicity pathways significantly modulated by 9D9 + epacadostat treatment compared with vehicle control, sorted by p-value and (G) the top five significantly regulated canonical pathways relative to vehicle identified by ingenuity pathway analysis (sorted by combination vs vehicle ascending p-values). There were no significant changes, and thus no activation of these canonical pathways, in the 9D9 vs vehicle group. PRR: pattern recognition receptor, ICOS: inducible T-cell costimulator ICOSL: inducible T-cell costimulatory ligand.

Article Snippet: The IDO1 inhibitor epacadostat (Chemscene, Monmouth Junction, NJ) was administered twice daily (6 hours between each dose) as an oral gavage formulation with 0.5% HPMC/0.25% Tween 20 in a water base at 100, 300 or 600 mg/kg/dose.

Techniques: Control, Activation Assay

Journal: The Febs Journal

Article Title: Pharmacological validation of TDO as a target for Parkinson’s disease

doi: 10.1111/febs.15721

Figure Lengend Snippet: Potency (IC 50 ) in n m of TDO inhibitors NTRC 3531‐0 and LM10 in biochemical and cell‐based assays for human (h) and mouse (m) TDO or IDO1. Confidence intervals and number of experimental replicates (n) are given within brackets

Article Snippet: The IDO1 inhibitor epacadostat, used as a reference inhibitor in the biochemical and cell‐based assays for IDO1, was purchased at MedKoo (cat. no. 206461).

Techniques: Inhibition

Journal: Cancers

Article Title: OATD-02 Validates the Benefits of Pharmacological Inhibition of Arginase 1 and 2 in Cancer

doi: 10.3390/cancers14163967

Figure Lengend Snippet: OATD-02 shows superior efficacy in the CT26 tumour model when combined with immune checkpoint inhibitor (anti-PD-L1 antibody) and IDO inhibitor (epacadostat). ( A )—BALB/c mice were inoculated with CT26 cells and upon 24 h dosed with OATD-02 (50 mg/kg, PO, BID) or epacadostat (30 mg/kg, PO, BID) till the end of the experiment; anti-PD-L1 antibody was administered at 2.5 mg/kg (IP, QD at days: 8, 10, 12, 14 and 16); ( B )—final measurements of tumour volumes were taken at day 24 post-inoculation and TGI was calculated (** 0.0042 < p < 0.0060, U Mann–Whitney test).

Article Snippet: The IDO1 inhibitor (epacadostat, INCB024360) was purchased from Shanghai Sunshine Chemical Technology (lot SSC151112) and used for oral gavage as a formulation containing 2% DMSO and 18% PEG400 in sterile saline.

Techniques: MANN-WHITNEY