Indoleamine 2,3-dioxygenase inhibitors: a patent review (2008 – 2012)

Dolušić, Eduard; Frédérick, Raphaël

doi:10.1517/13543776.2013.827662

Cited by 46 publications

(23 citation statements)

References 62 publications

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“…immunocompetent mice 9 and a dose-dependent reduction of kynurenine levels in patients with cancer in a phase I study. 10 INCB024360 is currently evaluated in phase II clinical trials as a single agent in ovarian cancer and in combination with the CTLA-4 antagonist ipilimumab in metastatic melanoma, clearly showing the potential of IDO1 inhibitors as a treatment option for cancer. 10 Similar to IDO1, expression of TDO by immunogenic mouse tumor cells prevented their rejection by preimmunized mice, and the effect could be reverted with an inhibitor.…”

Section: Introductionmentioning

confidence: 99%

“…10 INCB024360 is currently evaluated in phase II clinical trials as a single agent in ovarian cancer and in combination with the CTLA-4 antagonist ipilimumab in metastatic melanoma, clearly showing the potential of IDO1 inhibitors as a treatment option for cancer. 10 Similar to IDO1, expression of TDO by immunogenic mouse tumor cells prevented their rejection by preimmunized mice, and the effect could be reverted with an inhibitor. 11 Moreover, TDO is overexpressed in brain tumors, where it supports tumor growth and immune evasion by maintaining intratumoral kynurenine levels that activate the aryl hydrocarbon receptor and promote the generation of immune-suppressive T cells.…”

Section: Introductionmentioning

confidence: 99%

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High-Throughput Fluorescence-Based Screening Assays for Tryptophan-Catabolizing Enzymes

et al. 2014

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Indoleamine 2,3-dioxygenase (IDO1) and tryptophan 2,3-dioxygenase (TDO) are two structurally different enzymes that have a different tissue distribution and physiological roles, but both catalyze the conversion of tryptophan to N-formylkynurenine (NFK). IDO1 has been clinically validated as a small-molecule drug target for cancer, while preclinical studies indicate that TDO may be a target for cancer immunotherapy and neurodegenerative disease. We have developed a high-throughput screening assay for IDO1 and TDO based on a novel chemical probe, NFK Green, that reacts specifically with NFK to form a green fluorescent molecule with an excitation wavelength of 400 nm and an emission wavelength of 510 nm. We provide the first side-by-side comparison of a number of published inhibitors of IDO1 and TDO and reveal that the preclinical IDO1 inhibitor Compound 5l shows significant cross-reactivity with TDO, while the relative selectivity of other published inhibitors was confirmed. The suitability for high-throughput screening of the assays was demonstrated by screening a library of 87,000 chemical substances in 384-or 1536-well format. Finally, we demonstrate that the assay can also be used to measure the capacity of cells to metabolize tryptophan and to measure the cellular potency of IDO1 and TDO inhibitors.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

High-Throughput Fluorescence-Based Screening Assays for Tryptophan-Catabolizing Enzymes

et al. 2014

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“…Since removal of the two carbonyl groups has a detrimental effect on the inhibition potency of the chlorinated derivatives (see 5,6, and 16), we retained the C2 carbonyl group and explored the effect of substitutions at the C3 position alone. As before, the effect of C3 substitutions was assessed in the presence and absence of chlorines.…”

Section: Substitutions At C3mentioning

confidence: 99%

“…Due to the early identification of IDO1 as an enzyme with immunomodulatory function and its broad expression in the body, it became the main target for drug discovery. Many years of research have revealed a large number of IDO1 inhibitors with affinities that reach the low nanomolar region 1,[5][6][7][8] . Of these, the most promising candidate, known as INCB024360, is currently under investigation in clinical trials 9 .…”

Section: Introductionmentioning

confidence: 99%

Insights into the mechanism of inhibition of tryptophan 2,3-dioxygenase by isatin derivatives

Pantouris

Loudon-Griffiths

Mowat

2016

Journal of Enzyme Inhibition and Medicinal Chemistry

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Tryptophan 2,3-dioxygenase (TDO) is a cytosolic protein with a proven immunomodulatory function that promotes tumoral immune resistance and proliferation. Despite the interest in TDO as a therapeutic target in cancer treatment, the number of biologically useful inhibitors is limited. Herein, we report isatin derivatives as a new class of TDO inhibitors. Through structureactivity relationships and molecular docking studies, we optimized the inhibition potency of isatin derivatives by 4130-fold and elucidated the mechanistic details that control their mode of action. Hydrogen bond interactions between the compound and key active site residues of TDO, freedom upon rotation of the C3 chemical moiety and the presence of chlorines in the benzene ring of the compound comprise the properties that an isatin-based inhibitor requires to effectively inhibit the enzymatic activity of TDO.

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“…12) Although there were many basic studies on the IDO1 and IDO1 inhibitors, the studies on high throughput virtual screening (HTVS) for IDO1 inhibitors remained very few and most of them were done before 2012. 13,14) Here, we designed an effective HTVS protocol combining both pharmacophore modeling and molecular docking with the help of many basic studies after 2012 such as structure-activity relationship (SAR), binding modes and fresh released crystal structure.…”

mentioning

confidence: 99%

A Novel High Throughput Virtual Screening Protocol to Discover New Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors

Song

Yang

2017

CHEMICAL & PHARMACEUTICAL BULLETIN

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Indoleamine 2,3-dioxygenase 1 (IDO1) plays an important role in the immune escape of tumors and has emerged as a promising target for cancer immunotherapy. Despite its potential in immuno-oncology, very few chemotypes have been reported to date. Here, we disigned a novel high throughput virtual screening (HTVS) cascade protocol, combining both pharmacophore modeling and molecular docking and it was employed to query commercially available compounds to identify novel inhibitors. Among the 23 compounds selected for the in vitro IDO1 inhibitory activity assay, five compounds exhibit greater than 20% inhibition at a test concentration of 10 µM, with two compounds having an IC 50 value of 23.8 and 8.8 µM, respectively. The novel scaffold together with a ligand efficiency of 0.28 kcal/mol per heavy atom makes both compounds as suitable starting points for future chemistry elaboration. Our HTVS protocol was validated and could be employed in discovery of IDO1 inhibitors.

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Indoleamine 2,3-dioxygenase inhibitors: a patent review (2008 – 2012)

Cited by 46 publications

References 62 publications

High-Throughput Fluorescence-Based Screening Assays for Tryptophan-Catabolizing Enzymes

High-Throughput Fluorescence-Based Screening Assays for Tryptophan-Catabolizing Enzymes

Insights into the mechanism of inhibition of tryptophan 2,3-dioxygenase by isatin derivatives

A Novel High Throughput Virtual Screening Protocol to Discover New Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors

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