|
Inhibition of IDO1 (unknown origin)
|
Homo sapiens
|
72.0
nM
|
|
Journal : J. Med. Chem.
Title : Challenges and Opportunities in the Discovery of New Therapeutics Targeting the Kynurenine Pathway.
Year : 2015
Volume : 58
Issue : 22
First Page : 8762
Last Page : 8782
Authors : Dounay AB, Tuttle JB, Verhoest PR.
Abstract : The kynurenine pathway is responsible for the metabolism of more than 95% of dietary tryptophan (TRP) and produces numerous bioactive metabolites. Recent studies have focused on three enzymes in this pathway: indoleamine dioxygenase (IDO1), kynurenine monooxygenase (KMO), and kynurenine aminotransferase II (KAT II). IDO1 inhibitors are currently in clinical trials for the treatment of cancer, and these agents may also have therapeutic utility in neurological disorders, including multiple sclerosis. KMO inhibitors are being investigated as potential treatments for neurodegenerative diseases, such as Huntington's and Alzheimer's diseases. KAT II inhibitors have been proposed in new therapeutic approaches toward psychiatric and cognitive disorders, including cognitive impairment associated with schizophrenia. Numerous medicinal chemistry studies are currently aimed at the design of novel, potent, and selective inhibitors for each of these enzymes. The emerging opportunities and significant challenges associated with pharmacological modulation of these enzymes will be explored in this review.
|
Inhibition of N-terminal His-tagged human recombinant IDO1 expressed in Escherichia coli using D-tryptophan as substrate by methylene blue/ascorbate assay
|
Homo sapiens
|
72.0
nM
|
|
Journal : J. Med. Chem.
Title : Challenges in the Discovery of Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors.
Year : 2015
Volume : 58
Issue : 24
First Page : 9421
Last Page : 9437
Authors : Röhrig UF, Majjigapu SR, Vogel P, Zoete V, Michielin O.
Abstract : Since the discovery of indoleamine 2,3-dioxygenase 1 (IDO1) as an attractive target for anticancer therapy in 2003, the search for inhibitors has been intensely pursued both in academia and in pharmaceutical companies. Many novel IDO1 inhibitor scaffolds have been described, and a few potent compounds have entered clinical trials. However, a significant number of the reported compounds contain problematic functional groups, suggesting that enzyme inhibition could be the result of undesirable side reactions instead of selective binding to IDO1. Here, we describe issues in the employed experimental protocols, review and classify reported IDO1 inhibitors, and suggest different approaches for confirming viable inhibitor scaffolds.
|
Inhibition of IFN-gamma-stimulated IDO1 activity in human HeLa cells using L-tryptophan as substrate after 48 hrs by microplate reader analysis
|
Homo sapiens
|
7.1
nM
|
|
Journal : J. Med. Chem.
Title : Challenges in the Discovery of Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors.
Year : 2015
Volume : 58
Issue : 24
First Page : 9421
Last Page : 9437
Authors : Röhrig UF, Majjigapu SR, Vogel P, Zoete V, Michielin O.
Abstract : Since the discovery of indoleamine 2,3-dioxygenase 1 (IDO1) as an attractive target for anticancer therapy in 2003, the search for inhibitors has been intensely pursued both in academia and in pharmaceutical companies. Many novel IDO1 inhibitor scaffolds have been described, and a few potent compounds have entered clinical trials. However, a significant number of the reported compounds contain problematic functional groups, suggesting that enzyme inhibition could be the result of undesirable side reactions instead of selective binding to IDO1. Here, we describe issues in the employed experimental protocols, review and classify reported IDO1 inhibitors, and suggest different approaches for confirming viable inhibitor scaffolds.
|
Inhibition of recombinant human N-terminus IDO1 expressed in Escherichia coli assessed as N-formylkynurenine formation using L-tryptophan as substrate measured after 180 mins by UV absorbance based assay
|
Homo sapiens
|
67.0
nM
|
|
Journal : Bioorg Med Chem
Title : Discovery and preliminary structure-activity relationship of 1H-indazoles with promising indoleamine-2,3-dioxygenase 1 (IDO1) inhibition properties.
Year : 2016
Volume : 24
Issue : 23
First Page : 6194
Last Page : 6205
Authors : Qian S, He T, Wang W, He Y, Zhang M, Yang L, Li G, Wang Z.
Abstract : Indoleamine 2,3-dioxygenase 1 (IDO1)-mediated kynurenine pathway of tryptophan degradation is identified as an important immune effector pathway in the tumor cells to escape a potentially effective immune response. IDO1 is an attractive target for anticancer therapy and the discovery of IDO1 inhibitors has been intensely ongoing in both academic research laboratories and pharmaceutical organizations. Our study discovered that 1H-indazole was a novel key pharmacophore with potent IDO1 inhibitory activity. A series of new 1H-indazole derivatives were synthesized and determined the enzyme inhibitory activities, and the compound 2g exhibited the highest activity with an IC50 value of 5.3μM. The structure-activity relationships (SARs) analysis of the 1H-indazole derivatives as novel IDO1 inhibitors indicated that the 1H-indazole scaffold is necessary for IDO1 inhibition, and the substituent groups at the both 4-position and 6-position largely affect inhibitory activity. The docking model exhibited that the effective interactions of 1H-indazoles with ferrous ion of heme and key residues of hydrophobic Pocket A and B ensured the IDO1 inhibitory activities. The study suggested that the 1H-indazole was a novel interesting scaffold for IDO inhibition for further development.
|
Inhibition of recombinant human N-terminus IDO1 expressed in Escherichia coli assessed as N-formylkynurenine formation at 1 uM using L-tryptophan as substrate measured after 180 mins by UV absorbance based assay
|
Homo sapiens
|
97.0
%
|
|
Journal : Bioorg Med Chem
Title : Discovery and preliminary structure-activity relationship of 1H-indazoles with promising indoleamine-2,3-dioxygenase 1 (IDO1) inhibition properties.
Year : 2016
Volume : 24
Issue : 23
First Page : 6194
Last Page : 6205
Authors : Qian S, He T, Wang W, He Y, Zhang M, Yang L, Li G, Wang Z.
Abstract : Indoleamine 2,3-dioxygenase 1 (IDO1)-mediated kynurenine pathway of tryptophan degradation is identified as an important immune effector pathway in the tumor cells to escape a potentially effective immune response. IDO1 is an attractive target for anticancer therapy and the discovery of IDO1 inhibitors has been intensely ongoing in both academic research laboratories and pharmaceutical organizations. Our study discovered that 1H-indazole was a novel key pharmacophore with potent IDO1 inhibitory activity. A series of new 1H-indazole derivatives were synthesized and determined the enzyme inhibitory activities, and the compound 2g exhibited the highest activity with an IC50 value of 5.3μM. The structure-activity relationships (SARs) analysis of the 1H-indazole derivatives as novel IDO1 inhibitors indicated that the 1H-indazole scaffold is necessary for IDO1 inhibition, and the substituent groups at the both 4-position and 6-position largely affect inhibitory activity. The docking model exhibited that the effective interactions of 1H-indazoles with ferrous ion of heme and key residues of hydrophobic Pocket A and B ensured the IDO1 inhibitory activities. The study suggested that the 1H-indazole was a novel interesting scaffold for IDO inhibition for further development.
|
Inhibition of recombinant human N-terminus IDO1 expressed in Escherichia coli assessed as N-formylkynurenine formation at 10 uM using L-tryptophan as substrate measured after 180 mins by UV absorbance based assay
|
Homo sapiens
|
100.0
%
|
|
Journal : Bioorg Med Chem
Title : Discovery and preliminary structure-activity relationship of 1H-indazoles with promising indoleamine-2,3-dioxygenase 1 (IDO1) inhibition properties.
Year : 2016
Volume : 24
Issue : 23
First Page : 6194
Last Page : 6205
Authors : Qian S, He T, Wang W, He Y, Zhang M, Yang L, Li G, Wang Z.
Abstract : Indoleamine 2,3-dioxygenase 1 (IDO1)-mediated kynurenine pathway of tryptophan degradation is identified as an important immune effector pathway in the tumor cells to escape a potentially effective immune response. IDO1 is an attractive target for anticancer therapy and the discovery of IDO1 inhibitors has been intensely ongoing in both academic research laboratories and pharmaceutical organizations. Our study discovered that 1H-indazole was a novel key pharmacophore with potent IDO1 inhibitory activity. A series of new 1H-indazole derivatives were synthesized and determined the enzyme inhibitory activities, and the compound 2g exhibited the highest activity with an IC50 value of 5.3μM. The structure-activity relationships (SARs) analysis of the 1H-indazole derivatives as novel IDO1 inhibitors indicated that the 1H-indazole scaffold is necessary for IDO1 inhibition, and the substituent groups at the both 4-position and 6-position largely affect inhibitory activity. The docking model exhibited that the effective interactions of 1H-indazoles with ferrous ion of heme and key residues of hydrophobic Pocket A and B ensured the IDO1 inhibitory activities. The study suggested that the 1H-indazole was a novel interesting scaffold for IDO inhibition for further development.
|
Enzyme Assay: Human indoleamine 2,3-dioxygenasae (IDO) with an N-terminal His tag was expressed in E. coli and purified to homogeneity. IDO catalyzes the oxidative cleavage of the pyrrole ring of the indole nucleus of tryptophan to yield N′-formylkynurenine. The assays were performed at room temperature as described in the literature using 95 nM IDO and 2 mM D-Trp in the presence of 20 mM ascorbate, 5 μM methylene blue and 0.2 mg/mL catalase in 50 mM potassium phosphate buffer (pH 6.5). The initial reaction rates were recorded by continuously following the absorbance increase at 321 nm due to the formation of N′-formlylkynurenine (See: Sono, M., et al., 1980, J. Biol. Chem. 255, 1339-1345).
|
Homo sapiens
|
200.0
nM
|
|
Title : 1,2,5-oxadiazoles as inhibitors of indoleamine 2,3-dioxygenase
Year : 2016
|
Inhibition of human N-terminal His-tagged IDO1 expressed in Escherichia coli using D-Trp as substrate
|
Homo sapiens
|
73.0
nM
|
|
Journal : ACS Med Chem Lett
Title : INCB24360 (Epacadostat), a Highly Potent and Selective Indoleamine-2,3-dioxygenase 1 (IDO1) Inhibitor for Immuno-oncology.
Year : 2017
Volume : 8
Issue : 5
First Page : 486
Last Page : 491
Authors : Yue EW, Sparks R, Polam P, Modi D, Douty B, Wayland B, Glass B, Takvorian A, Glenn J, Zhu W, Bower M, Liu X, Leffet L, Wang Q, Bowman KJ, Hansbury MJ, Wei M, Li Y, Wynn R, Burn TC, Koblish HK, Fridman JS, Emm T, Scherle PA, Metcalf B, Combs AP.
Abstract : A data-centric medicinal chemistry approach led to the invention of a potent and selective IDO1 inhibitor 4f, INCB24360 (epacadostat). The molecular structure of INCB24360 contains several previously unknown or underutilized functional groups in drug substances, including a hydroxyamidine, furazan, bromide, and sulfamide. These moieties taken together in a single structure afford a compound that falls outside of "drug-like" space. Nevertheless, the in vitro ADME data is consistent with the good cell permeability and oral bioavailability observed in all species (rat, dog, monkey) tested. The extensive intramolecular hydrogen bonding observed in the small molecule crystal structure of 4f is believed to significantly contribute to the observed permeability and PK. Epacadostat in combination with anti-PD1 mAb pembrolizumab is currently being studied in a phase 3 clinical trial in patients with unresectable or metastatic melanoma.
|
Inhibition of IDO1 in IFN-gamma-stimulated human HeLa cells assessed as decrease in kynurenine levels after 48 hrs
|
Homo sapiens
|
7.4
nM
|
|
Journal : ACS Med Chem Lett
Title : INCB24360 (Epacadostat), a Highly Potent and Selective Indoleamine-2,3-dioxygenase 1 (IDO1) Inhibitor for Immuno-oncology.
Year : 2017
Volume : 8
Issue : 5
First Page : 486
Last Page : 491
Authors : Yue EW, Sparks R, Polam P, Modi D, Douty B, Wayland B, Glass B, Takvorian A, Glenn J, Zhu W, Bower M, Liu X, Leffet L, Wang Q, Bowman KJ, Hansbury MJ, Wei M, Li Y, Wynn R, Burn TC, Koblish HK, Fridman JS, Emm T, Scherle PA, Metcalf B, Combs AP.
Abstract : A data-centric medicinal chemistry approach led to the invention of a potent and selective IDO1 inhibitor 4f, INCB24360 (epacadostat). The molecular structure of INCB24360 contains several previously unknown or underutilized functional groups in drug substances, including a hydroxyamidine, furazan, bromide, and sulfamide. These moieties taken together in a single structure afford a compound that falls outside of "drug-like" space. Nevertheless, the in vitro ADME data is consistent with the good cell permeability and oral bioavailability observed in all species (rat, dog, monkey) tested. The extensive intramolecular hydrogen bonding observed in the small molecule crystal structure of 4f is believed to significantly contribute to the observed permeability and PK. Epacadostat in combination with anti-PD1 mAb pembrolizumab is currently being studied in a phase 3 clinical trial in patients with unresectable or metastatic melanoma.
|
Inhibition of IDO1 in IFN-gamma/LPS-stimulated human whole blood assessed as decrease in kynurenine levels preincubated for 15 mins followed by IFN-gamma/LPS stimulation for overnight by LC/MS/MS analysis
|
Homo sapiens
|
125.0
nM
|
|
Journal : ACS Med Chem Lett
Title : INCB24360 (Epacadostat), a Highly Potent and Selective Indoleamine-2,3-dioxygenase 1 (IDO1) Inhibitor for Immuno-oncology.
Year : 2017
Volume : 8
Issue : 5
First Page : 486
Last Page : 491
Authors : Yue EW, Sparks R, Polam P, Modi D, Douty B, Wayland B, Glass B, Takvorian A, Glenn J, Zhu W, Bower M, Liu X, Leffet L, Wang Q, Bowman KJ, Hansbury MJ, Wei M, Li Y, Wynn R, Burn TC, Koblish HK, Fridman JS, Emm T, Scherle PA, Metcalf B, Combs AP.
Abstract : A data-centric medicinal chemistry approach led to the invention of a potent and selective IDO1 inhibitor 4f, INCB24360 (epacadostat). The molecular structure of INCB24360 contains several previously unknown or underutilized functional groups in drug substances, including a hydroxyamidine, furazan, bromide, and sulfamide. These moieties taken together in a single structure afford a compound that falls outside of "drug-like" space. Nevertheless, the in vitro ADME data is consistent with the good cell permeability and oral bioavailability observed in all species (rat, dog, monkey) tested. The extensive intramolecular hydrogen bonding observed in the small molecule crystal structure of 4f is believed to significantly contribute to the observed permeability and PK. Epacadostat in combination with anti-PD1 mAb pembrolizumab is currently being studied in a phase 3 clinical trial in patients with unresectable or metastatic melanoma.
|
Inhibition of IDO1 in IFNgamma and LPS-stimulated human dendritic cells co-cultured with human T cells assessed as inhibition of T-cell proliferation in presence of soluble anti-CD3 antibody and human recombinant IL-2 incubated for 2 days
|
Homo sapiens
|
13.0
nM
|
|
Journal : Eur J Med Chem
Title : Recent discovery of indoleamine-2,3-dioxygenase 1 inhibitors targeting cancer immunotherapy.
Year : 2018
Volume : 143
First Page : 656
Last Page : 669
Authors : Weng T, Qiu X, Wang J, Li Z, Bian J.
Abstract : There has been great attention on indoleamine-2,3-dioxygenase 1 (IDO1) around cancer immunotherapy because of its role in enabling cancers to evade the immune system. The most recent spurt of high potent IDO1 inhibitors has been driven by the solution of the increased crystal structures of inhibitors with IDO1. Though the structural information of the active site of IDO1 obtained from the crystals are quite similar, the structures of reported potent inhibitors are quite different. Besides, while thousands of bioactive small molecule inhibitors of IDO1 exist, to date, only five compounds have entered clinical trials. In an effort to obtain more clinical drugs targeting IDO1, more comprehensive understanding of the active site of IDO1 and the structures of existing potent IDO1 inhibitors are necessary. Thus, this review mainly focus on the key features reported from specific crystal structures of IDO1 and an overview of the most recently developed IDO1 inhibitors under investigation and their other derived applications which may contribute to a better usage in cancer immunotherapy.
|
Inhibition of human IDO1 expressed in HEK293/MSR cells assessed as reduction in kynurenine production incubated fro 2 days
|
Homo sapiens
|
15.0
nM
|
|
Journal : Eur J Med Chem
Title : Recent discovery of indoleamine-2,3-dioxygenase 1 inhibitors targeting cancer immunotherapy.
Year : 2018
Volume : 143
First Page : 656
Last Page : 669
Authors : Weng T, Qiu X, Wang J, Li Z, Bian J.
Abstract : There has been great attention on indoleamine-2,3-dioxygenase 1 (IDO1) around cancer immunotherapy because of its role in enabling cancers to evade the immune system. The most recent spurt of high potent IDO1 inhibitors has been driven by the solution of the increased crystal structures of inhibitors with IDO1. Though the structural information of the active site of IDO1 obtained from the crystals are quite similar, the structures of reported potent inhibitors are quite different. Besides, while thousands of bioactive small molecule inhibitors of IDO1 exist, to date, only five compounds have entered clinical trials. In an effort to obtain more clinical drugs targeting IDO1, more comprehensive understanding of the active site of IDO1 and the structures of existing potent IDO1 inhibitors are necessary. Thus, this review mainly focus on the key features reported from specific crystal structures of IDO1 and an overview of the most recently developed IDO1 inhibitors under investigation and their other derived applications which may contribute to a better usage in cancer immunotherapy.
|
Inhibition of IDO1 in IFNgamma-stimulated human OCI-AML2 cells assessed as reduction in kynurenine production
|
Homo sapiens
|
3.4
nM
|
|
Journal : Eur J Med Chem
Title : Recent discovery of indoleamine-2,3-dioxygenase 1 inhibitors targeting cancer immunotherapy.
Year : 2018
Volume : 143
First Page : 656
Last Page : 669
Authors : Weng T, Qiu X, Wang J, Li Z, Bian J.
Abstract : There has been great attention on indoleamine-2,3-dioxygenase 1 (IDO1) around cancer immunotherapy because of its role in enabling cancers to evade the immune system. The most recent spurt of high potent IDO1 inhibitors has been driven by the solution of the increased crystal structures of inhibitors with IDO1. Though the structural information of the active site of IDO1 obtained from the crystals are quite similar, the structures of reported potent inhibitors are quite different. Besides, while thousands of bioactive small molecule inhibitors of IDO1 exist, to date, only five compounds have entered clinical trials. In an effort to obtain more clinical drugs targeting IDO1, more comprehensive understanding of the active site of IDO1 and the structures of existing potent IDO1 inhibitors are necessary. Thus, this review mainly focus on the key features reported from specific crystal structures of IDO1 and an overview of the most recently developed IDO1 inhibitors under investigation and their other derived applications which may contribute to a better usage in cancer immunotherapy.
|
Inhibition of IDO1 in IFNgamma-stimulated human THP1 cells assessed as reduction in kynurenine productio by spectrophotometric analysis
|
Homo sapiens
|
23.0
nM
|
|
Journal : Eur J Med Chem
Title : Recent discovery of indoleamine-2,3-dioxygenase 1 inhibitors targeting cancer immunotherapy.
Year : 2018
Volume : 143
First Page : 656
Last Page : 669
Authors : Weng T, Qiu X, Wang J, Li Z, Bian J.
Abstract : There has been great attention on indoleamine-2,3-dioxygenase 1 (IDO1) around cancer immunotherapy because of its role in enabling cancers to evade the immune system. The most recent spurt of high potent IDO1 inhibitors has been driven by the solution of the increased crystal structures of inhibitors with IDO1. Though the structural information of the active site of IDO1 obtained from the crystals are quite similar, the structures of reported potent inhibitors are quite different. Besides, while thousands of bioactive small molecule inhibitors of IDO1 exist, to date, only five compounds have entered clinical trials. In an effort to obtain more clinical drugs targeting IDO1, more comprehensive understanding of the active site of IDO1 and the structures of existing potent IDO1 inhibitors are necessary. Thus, this review mainly focus on the key features reported from specific crystal structures of IDO1 and an overview of the most recently developed IDO1 inhibitors under investigation and their other derived applications which may contribute to a better usage in cancer immunotherapy.
|
Inhibition of IDO1 (unknown origin) using D-tryptophan as substrate by spectrophotometric analysis
|
Homo sapiens
|
72.0
nM
|
|
Journal : Eur J Med Chem
Title : Recent discovery of indoleamine-2,3-dioxygenase 1 inhibitors targeting cancer immunotherapy.
Year : 2018
Volume : 143
First Page : 656
Last Page : 669
Authors : Weng T, Qiu X, Wang J, Li Z, Bian J.
Abstract : There has been great attention on indoleamine-2,3-dioxygenase 1 (IDO1) around cancer immunotherapy because of its role in enabling cancers to evade the immune system. The most recent spurt of high potent IDO1 inhibitors has been driven by the solution of the increased crystal structures of inhibitors with IDO1. Though the structural information of the active site of IDO1 obtained from the crystals are quite similar, the structures of reported potent inhibitors are quite different. Besides, while thousands of bioactive small molecule inhibitors of IDO1 exist, to date, only five compounds have entered clinical trials. In an effort to obtain more clinical drugs targeting IDO1, more comprehensive understanding of the active site of IDO1 and the structures of existing potent IDO1 inhibitors are necessary. Thus, this review mainly focus on the key features reported from specific crystal structures of IDO1 and an overview of the most recently developed IDO1 inhibitors under investigation and their other derived applications which may contribute to a better usage in cancer immunotherapy.
|
Inhibition of IDO1 in recombinant human IFNgamma and LPS-induced human HeLa assessed as reduction in kynurenine production incubated for 2 days by spectrophotometric analysis
|
Homo sapiens
|
7.1
nM
|
|
Journal : Eur J Med Chem
Title : Recent discovery of indoleamine-2,3-dioxygenase 1 inhibitors targeting cancer immunotherapy.
Year : 2018
Volume : 143
First Page : 656
Last Page : 669
Authors : Weng T, Qiu X, Wang J, Li Z, Bian J.
Abstract : There has been great attention on indoleamine-2,3-dioxygenase 1 (IDO1) around cancer immunotherapy because of its role in enabling cancers to evade the immune system. The most recent spurt of high potent IDO1 inhibitors has been driven by the solution of the increased crystal structures of inhibitors with IDO1. Though the structural information of the active site of IDO1 obtained from the crystals are quite similar, the structures of reported potent inhibitors are quite different. Besides, while thousands of bioactive small molecule inhibitors of IDO1 exist, to date, only five compounds have entered clinical trials. In an effort to obtain more clinical drugs targeting IDO1, more comprehensive understanding of the active site of IDO1 and the structures of existing potent IDO1 inhibitors are necessary. Thus, this review mainly focus on the key features reported from specific crystal structures of IDO1 and an overview of the most recently developed IDO1 inhibitors under investigation and their other derived applications which may contribute to a better usage in cancer immunotherapy.
|
Inhibition of human IDO1 expressed in HEK293 cells assessed as reduction in kynurenine production after 30 mins
|
Homo sapiens
|
8.74
nM
|
|
Journal : ACS Med Chem Lett
Title : Identification of Potent Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors Based on a Phenylimidazole Scaffold.
Year : 2018
Volume : 9
Issue : 2
First Page : 131
Last Page : 136
Authors : Brant MG, Goodwin-Tindall J, Stover KR, Stafford PM, Wu F, Meek AR, Schiavini P, Wohnig S, Weaver DF.
Abstract : Inhibition of indoleamine 2,3-dioxygenase (IDO1) is an attractive immunotherapeutic approach for the treatment of a variety of cancers. Dysregulation of this enzyme has also been implicated in other disorders including Alzheimer's disease and arthritis. Herein, we report the structure-based design of two related series of molecules: N1-substituted 5-indoleimidazoles and N1-substituted 5-phenylimidazoles. The latter (and more potent) series was accessed through an unexpected rearrangement of an imine intermediate during a Van Leusen imidazole synthesis reaction. Evidence for the binding modes for both inhibitor series is supported by computational and structure-activity relationship studies.
|
Inhibition of human recombinant IDO1 assessed as reduction in kynurenine production at 1 uM using L-tryptophan incubated for 60 mins by Ehrlich's reagent based assay
|
Homo sapiens
|
100.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : A multicomponent approach in the discovery of indoleamine 2,3-dioxygenase 1 inhibitors: Synthesis, biological investigation and docking studies.
Year : 2018
Volume : 28
Issue : 4
First Page : 651
Last Page : 657
Authors : Griglio A, Torre E, Serafini M, Bianchi A, Schmid R, Coda Zabetta G, Massarotti A, Sorba G, Pirali T, Fallarini S.
Abstract : Indoleamine 2,3-dioxygenase plays a crucial role in immune tolerance and has emerged as an attractive target for cancer immunotherapy. In this study, the Passerini and Ugi multicomponent reactions have been employed to assemble a small library of imidazothiazoles that target IDO1. While the p-bromophenyl and the imidazothiazole moieties have been kept fixed, a full SAR study has been performed on the side-chain, leading to the discovery of nine compounds with sub-micromolar IC50 values in the enzyme-based assay. Compound 7d, displaying a α-acyloxyamide substructure, is the most potent compound, with an IC50 value of 0.20 µM, but a low activity in a cell-based assay. Compound 6o, containing a α-acylaminoamide moiety, shows an IC50 value of 0.81 µM in the IDO1-based assay, a full biocompatibility at 10 µM, together with a modest inhibitory activity in A375 cells. Molecular docking studies show that both 7d and 6o display a unique binding mode in the IDO1 active site, with the side-chain protruding in an additional pocket C, where a crucial hydrogen bond is formed with Lys238. Overall, this work describes an isocyanide based-multicomponent approach as a straightforward and versatile tool to rapidly access IDO1 inhibitors, providing a new direction for their future design and development.
|
Inhibition of human recombinant IDO1 assessed as reduction in kynurenine production using L-tryptophan incubated for 60 mins by Ehrlich's reagent based assay
|
Homo sapiens
|
10.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : A multicomponent approach in the discovery of indoleamine 2,3-dioxygenase 1 inhibitors: Synthesis, biological investigation and docking studies.
Year : 2018
Volume : 28
Issue : 4
First Page : 651
Last Page : 657
Authors : Griglio A, Torre E, Serafini M, Bianchi A, Schmid R, Coda Zabetta G, Massarotti A, Sorba G, Pirali T, Fallarini S.
Abstract : Indoleamine 2,3-dioxygenase plays a crucial role in immune tolerance and has emerged as an attractive target for cancer immunotherapy. In this study, the Passerini and Ugi multicomponent reactions have been employed to assemble a small library of imidazothiazoles that target IDO1. While the p-bromophenyl and the imidazothiazole moieties have been kept fixed, a full SAR study has been performed on the side-chain, leading to the discovery of nine compounds with sub-micromolar IC50 values in the enzyme-based assay. Compound 7d, displaying a α-acyloxyamide substructure, is the most potent compound, with an IC50 value of 0.20 µM, but a low activity in a cell-based assay. Compound 6o, containing a α-acylaminoamide moiety, shows an IC50 value of 0.81 µM in the IDO1-based assay, a full biocompatibility at 10 µM, together with a modest inhibitory activity in A375 cells. Molecular docking studies show that both 7d and 6o display a unique binding mode in the IDO1 active site, with the side-chain protruding in an additional pocket C, where a crucial hydrogen bond is formed with Lys238. Overall, this work describes an isocyanide based-multicomponent approach as a straightforward and versatile tool to rapidly access IDO1 inhibitors, providing a new direction for their future design and development.
|
Inhibition of IDO1 in IFN-gamma-stimulated human A375 cells assessed as decrease in L-kynurenine levels at 10 uM in presence of L-Trp incubated for 48 hrs by HPLC method
|
Homo sapiens
|
100.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : A multicomponent approach in the discovery of indoleamine 2,3-dioxygenase 1 inhibitors: Synthesis, biological investigation and docking studies.
Year : 2018
Volume : 28
Issue : 4
First Page : 651
Last Page : 657
Authors : Griglio A, Torre E, Serafini M, Bianchi A, Schmid R, Coda Zabetta G, Massarotti A, Sorba G, Pirali T, Fallarini S.
Abstract : Indoleamine 2,3-dioxygenase plays a crucial role in immune tolerance and has emerged as an attractive target for cancer immunotherapy. In this study, the Passerini and Ugi multicomponent reactions have been employed to assemble a small library of imidazothiazoles that target IDO1. While the p-bromophenyl and the imidazothiazole moieties have been kept fixed, a full SAR study has been performed on the side-chain, leading to the discovery of nine compounds with sub-micromolar IC50 values in the enzyme-based assay. Compound 7d, displaying a α-acyloxyamide substructure, is the most potent compound, with an IC50 value of 0.20 µM, but a low activity in a cell-based assay. Compound 6o, containing a α-acylaminoamide moiety, shows an IC50 value of 0.81 µM in the IDO1-based assay, a full biocompatibility at 10 µM, together with a modest inhibitory activity in A375 cells. Molecular docking studies show that both 7d and 6o display a unique binding mode in the IDO1 active site, with the side-chain protruding in an additional pocket C, where a crucial hydrogen bond is formed with Lys238. Overall, this work describes an isocyanide based-multicomponent approach as a straightforward and versatile tool to rapidly access IDO1 inhibitors, providing a new direction for their future design and development.
|
Inhibition of recombinant human GST-tagged IDO1 (1 to 404 residues) using D-Tryptophan as substrate
|
Homo sapiens
|
77.8
nM
|
|
Journal : ACS Med Chem Lett
Title : Discovery of Novel Indoleamine 2,3-Dioxygenase 1 (IDO1) and Histone Deacetylase (HDAC) Dual Inhibitors.
Year : 2018
Volume : 9
Issue : 4
First Page : 312
Last Page : 317
Authors : Fang K, Dong G, Li Y, He S, Wu Y, Wu S, Wang W, Sheng C.
Abstract : In order to take advantage of both immunotherapeutic and epigenetic antitumor agents, the first generation of dual indoleamine 2,3-dioxygenase 1 (IDO1) and histone deacetylase (HDAC) inhibitors were designed. The highly active dual inhibitor 10 showed excellent and balanced activity against both IDO1 (IC50 = 69.0 nM) and HDAC1 (IC50 = 66.5 nM), whose dual targeting mechanisms were validated in cancer cells. Compound 10 had good pharmacokinetic profiles as an orally active antitumor agent and significantly reduced the l-kynurenine level in plasma. In particular, it showed excellent in vivo antitumor efficacy in the murine LLC tumor model with low toxicity. This proof-of-concept study provided a novel strategy for cancer treatment. Compound 10 represents a promising lead compound for the development of novel antitumor agents and can also be used as a valuable probe to clarify the relationships and mechanisms between cancer immunotherapy and epigenetics.
|
In vivo inhibition of IDO1 in wild type C57BL/6 mouse assessed as reduction in kynurenine levels in plasma at 100 mg/kg, po administered via gavage after 8 hrs by LC-MS/MS analysis
|
Mus musculus
|
50.0
%
|
|
Journal : ACS Med Chem Lett
Title : Discovery of Novel Indoleamine 2,3-Dioxygenase 1 (IDO1) and Histone Deacetylase (HDAC) Dual Inhibitors.
Year : 2018
Volume : 9
Issue : 4
First Page : 312
Last Page : 317
Authors : Fang K, Dong G, Li Y, He S, Wu Y, Wu S, Wang W, Sheng C.
Abstract : In order to take advantage of both immunotherapeutic and epigenetic antitumor agents, the first generation of dual indoleamine 2,3-dioxygenase 1 (IDO1) and histone deacetylase (HDAC) inhibitors were designed. The highly active dual inhibitor 10 showed excellent and balanced activity against both IDO1 (IC50 = 69.0 nM) and HDAC1 (IC50 = 66.5 nM), whose dual targeting mechanisms were validated in cancer cells. Compound 10 had good pharmacokinetic profiles as an orally active antitumor agent and significantly reduced the l-kynurenine level in plasma. In particular, it showed excellent in vivo antitumor efficacy in the murine LLC tumor model with low toxicity. This proof-of-concept study provided a novel strategy for cancer treatment. Compound 10 represents a promising lead compound for the development of novel antitumor agents and can also be used as a valuable probe to clarify the relationships and mechanisms between cancer immunotherapy and epigenetics.
|
Inhibition of human IDO1 using D-Trp as substrate
|
Homo sapiens
|
64.6
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and biological evaluation of novel naphthoquinone derivatives as IDO1 inhibitors.
Year : 2018
Volume : 157
First Page : 423
Last Page : 436
Authors : Pan L, Zheng Q, Chen Y, Yang R, Yang Y, Li Z, Meng X.
Abstract : Indoleamine 2,3-dioxygenase 1 (IDO1) mediated kynurenine pathway of tryptophan degradation is identified as an appealing and novel target in immunotherapy for the treatment of cancer. In this study, a novel series of naphthoquinone derivatives were synthesized, characterized and evaluated for their inhibitory activities against IDO1, and their structure-activity relationship was investigated. Among them, compounds T16, T44, T47, T49, T53 and T54 displayed potent IDO1 inhibitory activities with IC50 values ranging between 18 and 61 nM, which are more potent than INCB024360 undergoing clinical trial III evaluation. In addition, compounds T28, T44 and T53 decreased the kynurenine levels in rat plasma by 30%-50%. Compounds exhibiting excellent IDO1 inhibitory activities were also evaluated for their inhibitory activities against tryptophan 2,3-dioxygenase (TDO). Of which, compound T28 (IDO1 IC50 = 120 nM) showed promising TDO inhibition (IC50 72 nM) and was identified as an IDO1/TDO dual inhibitor.
|
Inhibition of human IDO1 at 1 uM using D-Trp as substrate
|
Homo sapiens
|
93.0
%
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and biological evaluation of novel naphthoquinone derivatives as IDO1 inhibitors.
Year : 2018
Volume : 157
First Page : 423
Last Page : 436
Authors : Pan L, Zheng Q, Chen Y, Yang R, Yang Y, Li Z, Meng X.
Abstract : Indoleamine 2,3-dioxygenase 1 (IDO1) mediated kynurenine pathway of tryptophan degradation is identified as an appealing and novel target in immunotherapy for the treatment of cancer. In this study, a novel series of naphthoquinone derivatives were synthesized, characterized and evaluated for their inhibitory activities against IDO1, and their structure-activity relationship was investigated. Among them, compounds T16, T44, T47, T49, T53 and T54 displayed potent IDO1 inhibitory activities with IC50 values ranging between 18 and 61 nM, which are more potent than INCB024360 undergoing clinical trial III evaluation. In addition, compounds T28, T44 and T53 decreased the kynurenine levels in rat plasma by 30%-50%. Compounds exhibiting excellent IDO1 inhibitory activities were also evaluated for their inhibitory activities against tryptophan 2,3-dioxygenase (TDO). Of which, compound T28 (IDO1 IC50 = 120 nM) showed promising TDO inhibition (IC50 72 nM) and was identified as an IDO1/TDO dual inhibitor.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of Caco-2 cells at 10 uM after 48 hours by high content imaging
|
Homo sapiens
|
-8.22
%
|
|
Title : Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection
Year : 2020
Authors : Bernhard Ellinger, Denisa Bojkova, Andrea Zaliani, Jindrich Cinatl, Carsten Claussen, Sandra Westhaus, Jeanette Reinshagen, Maria Kuzikov, Markus Wolf, Gerd Geisslinger, Philip Gribbon, Sandra Ciesek
Abstract : To identify possible candidates for progression towards clinical studies against SARS-CoV-2, we screened a well-defined collection of 5632 compounds including 3488 compounds which have undergone clinical investigations (marketed drugs, phases 1 -3, and withdrawn) across 600 indications. Compounds were screened for their inhibition of viral induced cytotoxicity using the human epithelial colorectal adenocarcinoma cell line Caco-2 and a SARS-CoV-2 isolate. The primary screen of 5632 compounds gave 271 hits. A total of 64 compounds with IC50 <20 µM were identified, including 19 compounds with IC50 < 1 µM. Of this confirmed hit population, 90% have not yet been previously reported as active against SARS-CoV-2 in-vitro cell assays. Some 37 of the actives are launched drugs, 19 are in phases 1-3 and 10 pre-clinical. Several inhibitors were associated with modulation of host pathways including kinase signaling P53 activation, ubiquitin pathways and PDE activity modulation, with long chain acyl transferases were effective viral inhibitors.
|
Inhibition of IDO1 in human HeLa cells using L-tryptophan as substrate after 20 hrs
|
Homo sapiens
|
70.0
nM
|
|
Journal : Eur J Med Chem
Title : Diaryl hydroxylamines as pan or dual inhibitors of indoleamine 2,3-dioxygenase-1, indoleamine 2,3-dioxygenase-2 and tryptophan dioxygenase.
Year : 2019
Volume : 162
First Page : 455
Last Page : 464
Authors : Winters M, DuHadaway JB, Pham KN, Lewis-Ballester A, Badir S, Wai J, Sheikh E, Yeh SR, Prendergast GC, Muller AJ, Malachowski WP.
Abstract : Tryptophan (Trp) catabolizing enzymes play an important and complex role in the development of cancer. Significant evidence implicates them in a range of inflammatory and immunosuppressive activities. Whereas inhibitors of indoleamine 2,3-dioxygenase-1 (IDO1) have been reported and analyzed in the clinic, fewer inhibitors have been described for tryptophan dioxygenase (TDO) and indoleamine 2,3-dioxygenase-2 (IDO2) which also have been implicated more recently in cancer, inflammation and immune control. Consequently the development of dual or pan inhibitors of these Trp catabolizing enzymes may represent a therapeutically important area of research. This is the first report to describe the development of dual and pan inhibitors of IDO1, TDO and IDO2.
|
Inhibition of human N-terminal GST-tagged IDO1 expressed in Escherichia coli Rosetta(DE3) pLysS using L-tryptophan as substrate measured after 1 hr by fluorescence assay
|
Homo sapiens
|
73.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Discovery of Hydroxyamidine Based Inhibitors of IDO1 for Cancer Immunotherapy with Reduced Potential for Glucuronidation.
Year : 2020
Volume : 11
Issue : 2
First Page : 179
Last Page : 187
Authors : Steeneck C, Kinzel O, Anderhub S, Hornberger M, Pinto S, Morschhaeuser B, Braun F, Kleymann G, Hoffmann T.
Abstract : Following the impressive success of checkpoint inhibitors in the treatment of cancer, combinations of IDO1 inhibitors with PD-1/PD-L1 antibodies are in clinical development aiming to increase response rates. Using the hydroxyamidine pharmacophore of the IDO1 inhibitor INCB14943 as a starting point for the design of new inhibitors, the potential shortcomings of extensive hydroxyamidine glucuronidation in humans was addressed. Compounds were optimized using a stability assay with recombinant UGT1A9 enzyme together with the measurement of glucuronide formation in human hepatocytes. Optimized analog 24 showed cellular and biochemical IDO1 IC50 values in the low nanomolar range, a suitable in vitro ADME/PK profile, and efficacy in an animal model of cancer. In a humanized liver mouse model the lead compound exhibited significantly reduced glucuronidation compared to epacadostat (2).
|
Inhibition of IDO1 in interferon-gamma-induced human SKOV3 cells assessed as N-formylkynurenine formation using L-tryptophan as substrate measured after 24 hrs by fluorescence assay
|
Homo sapiens
|
7.9
nM
|
|
Journal : ACS Med Chem Lett
Title : Discovery of Hydroxyamidine Based Inhibitors of IDO1 for Cancer Immunotherapy with Reduced Potential for Glucuronidation.
Year : 2020
Volume : 11
Issue : 2
First Page : 179
Last Page : 187
Authors : Steeneck C, Kinzel O, Anderhub S, Hornberger M, Pinto S, Morschhaeuser B, Braun F, Kleymann G, Hoffmann T.
Abstract : Following the impressive success of checkpoint inhibitors in the treatment of cancer, combinations of IDO1 inhibitors with PD-1/PD-L1 antibodies are in clinical development aiming to increase response rates. Using the hydroxyamidine pharmacophore of the IDO1 inhibitor INCB14943 as a starting point for the design of new inhibitors, the potential shortcomings of extensive hydroxyamidine glucuronidation in humans was addressed. Compounds were optimized using a stability assay with recombinant UGT1A9 enzyme together with the measurement of glucuronide formation in human hepatocytes. Optimized analog 24 showed cellular and biochemical IDO1 IC50 values in the low nanomolar range, a suitable in vitro ADME/PK profile, and efficacy in an animal model of cancer. In a humanized liver mouse model the lead compound exhibited significantly reduced glucuronidation compared to epacadostat (2).
|
Inhibition of IDO1 in interferon-gamma-induced human HeLa cells at 1 uM using L-tryptophan substrate incubated for 24 hrs relative to untreated control
|
Homo sapiens
|
98.1
%
|
|
Journal : Bioorg Med Chem
Title : Design, synthesis and biological evaluation of novel aryl-acrylic derivatives as novel indoleamine-2,3-dioxygenase 1 (IDO1) inhibitors.
Year : 2019
Volume : 27
Issue : 14
First Page : 3135
Last Page : 3144
Authors : Hu H, Li M, Wu D, Li Z, Miao R, Liu Y, Gong P.
Abstract : Two series of novel aryl-acrylic derivatives were designed, synthesized, and screened in enzymatic and cellular inhibitory activities. All compounds showed moderate to significant potency. The SAR analyses indicated that the semicarbazone linker is better than the 1,2,3-triazole linker. Among semicarbazone compounds that R<sub>1</sub> bearing di-chain amino groups exhibited superior activities to those with morpholino group. Furthermore, compounds with electron-withdrawing groups at the 2-position or 4-position on the terminal phenyl ring were more active. Among these, compounds 7g, 7i, 7m and 7n exhibited the inhibitory potency in the low micromolar range and displayed negligible level of cytotoxicity against normal HeLa cells. In addition, the study suggested that the aryl-acrylic is an interesting novel scaffold for IDO1 inhibition for further development.
|
Inhibition of IDO1 in interferon-gamma-induced human HeLa cells at 10 uM using L-tryptophan substrate incubated for 24 hrs relative to untreated control
|
Homo sapiens
|
101.2
%
|
|
Journal : Bioorg Med Chem
Title : Design, synthesis and biological evaluation of novel aryl-acrylic derivatives as novel indoleamine-2,3-dioxygenase 1 (IDO1) inhibitors.
Year : 2019
Volume : 27
Issue : 14
First Page : 3135
Last Page : 3144
Authors : Hu H, Li M, Wu D, Li Z, Miao R, Liu Y, Gong P.
Abstract : Two series of novel aryl-acrylic derivatives were designed, synthesized, and screened in enzymatic and cellular inhibitory activities. All compounds showed moderate to significant potency. The SAR analyses indicated that the semicarbazone linker is better than the 1,2,3-triazole linker. Among semicarbazone compounds that R<sub>1</sub> bearing di-chain amino groups exhibited superior activities to those with morpholino group. Furthermore, compounds with electron-withdrawing groups at the 2-position or 4-position on the terminal phenyl ring were more active. Among these, compounds 7g, 7i, 7m and 7n exhibited the inhibitory potency in the low micromolar range and displayed negligible level of cytotoxicity against normal HeLa cells. In addition, the study suggested that the aryl-acrylic is an interesting novel scaffold for IDO1 inhibition for further development.
|
Inhibition of recombinant human IDO1 expressed in Escherichia coli BL21 cells using L-tryptophan as substrate incubated for 30 mins by methylene blue dye based microplate reader analysis
|
Homo sapiens
|
40.9
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and antitumor study of a series of N-Cyclic sulfamoylaminoethyl substituted 1,2,5-oxadiazol-3-amines as new indoleamine 2, 3-dioxygenase 1 (IDO1) inhibitors.
Year : 2019
Volume : 179
First Page : 38
Last Page : 55
Authors : Chen S, Guo W, Liu X, Sun P, Wang Y, Ding C, Meng L, Zhang A.
Abstract : Indoleamine 2, 3-dioxygenase 1 (IDO1) plays a key role in tryptophan catabolism which is an important mechanism in immune tolerance. The small molecule epacadostat is the most advanced IDO1 inhibitor, but its phase III trials as a single agent or in combinations with PD-1 antibody failed to show appreciable objective responses. To gain more insight on the antitumor efficacy of IDO1 inhibitors, we have designed a series of analogues of epacadostat by incorporating a cyclic aminosulfonamide moiety as the sidechain capping functionality. Compound 5a was found to display significant potency against recombinant hIDO1 and hIDO1 expressed HEK293 cancer cells. This compound has improved physico-chemical properties, acceptable PK parameters as well as optimal cardiac safety. Similar to epacadostat, 5a is ineffective as single agent in the CT-26 syngeneic xenograft model, however, the combination of 5a with PD-1 antibody showed both elevated tumor growth inhibition and prolonged median life span.
|
Inhibition of recombinant human IDO1 expressed in HEK293 cells assessed as N-formylkynurenine formation by measuring kynurenine level incubated for 12 hrs by microplate reader analysis
|
Homo sapiens
|
12.6
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and antitumor study of a series of N-Cyclic sulfamoylaminoethyl substituted 1,2,5-oxadiazol-3-amines as new indoleamine 2, 3-dioxygenase 1 (IDO1) inhibitors.
Year : 2019
Volume : 179
First Page : 38
Last Page : 55
Authors : Chen S, Guo W, Liu X, Sun P, Wang Y, Ding C, Meng L, Zhang A.
Abstract : Indoleamine 2, 3-dioxygenase 1 (IDO1) plays a key role in tryptophan catabolism which is an important mechanism in immune tolerance. The small molecule epacadostat is the most advanced IDO1 inhibitor, but its phase III trials as a single agent or in combinations with PD-1 antibody failed to show appreciable objective responses. To gain more insight on the antitumor efficacy of IDO1 inhibitors, we have designed a series of analogues of epacadostat by incorporating a cyclic aminosulfonamide moiety as the sidechain capping functionality. Compound 5a was found to display significant potency against recombinant hIDO1 and hIDO1 expressed HEK293 cancer cells. This compound has improved physico-chemical properties, acceptable PK parameters as well as optimal cardiac safety. Similar to epacadostat, 5a is ineffective as single agent in the CT-26 syngeneic xenograft model, however, the combination of 5a with PD-1 antibody showed both elevated tumor growth inhibition and prolonged median life span.
|
Antitumour activity against mouse CT26 cells allografted in Balb/c mouse assessed as tumour growth inhibition at 100 mg/kg, po bid for 14 days starting 8 days post inoculation measured thrice per week relative to control
|
Mus musculus
|
81.2
%
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and antitumor study of a series of N-Cyclic sulfamoylaminoethyl substituted 1,2,5-oxadiazol-3-amines as new indoleamine 2, 3-dioxygenase 1 (IDO1) inhibitors.
Year : 2019
Volume : 179
First Page : 38
Last Page : 55
Authors : Chen S, Guo W, Liu X, Sun P, Wang Y, Ding C, Meng L, Zhang A.
Abstract : Indoleamine 2, 3-dioxygenase 1 (IDO1) plays a key role in tryptophan catabolism which is an important mechanism in immune tolerance. The small molecule epacadostat is the most advanced IDO1 inhibitor, but its phase III trials as a single agent or in combinations with PD-1 antibody failed to show appreciable objective responses. To gain more insight on the antitumor efficacy of IDO1 inhibitors, we have designed a series of analogues of epacadostat by incorporating a cyclic aminosulfonamide moiety as the sidechain capping functionality. Compound 5a was found to display significant potency against recombinant hIDO1 and hIDO1 expressed HEK293 cancer cells. This compound has improved physico-chemical properties, acceptable PK parameters as well as optimal cardiac safety. Similar to epacadostat, 5a is ineffective as single agent in the CT-26 syngeneic xenograft model, however, the combination of 5a with PD-1 antibody showed both elevated tumor growth inhibition and prolonged median life span.
|
Inhibition of recombinant human IDO1 expressed in Escherichia coli BL21 cells assessed as reduction in conversion of L-tryptophan to N-formyl kynurenine using L-tryptophan as substrate after 30 mins by methylene blue dye based microplate reader analysis
|
Homo sapiens
|
70.0
nM
|
|
Journal : J Med Chem
Title : N-Benzyl/Aryl Substituted Tryptanthrin as Dual Inhibitors of Indoleamine 2,3-Dioxygenase and Tryptophan 2,3-Dioxygenase.
Year : 2019
Volume : 62
Issue : 20
First Page : 9161
Last Page : 9174
Authors : Yang D, Zhang S, Fang X, Guo L, Hu N, Guo Z, Li X, Yang S, He JC, Kuang C, Yang Q.
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.
|
Inhibition of IDO1 in IFN-gamma stimulated human HeLa cells assessed as reduction in kynurenine production incubated for 18 hrs
|
Homo sapiens
|
7.0
nM
|
|
Journal : J Med Chem
Title : N-Benzyl/Aryl Substituted Tryptanthrin as Dual Inhibitors of Indoleamine 2,3-Dioxygenase and Tryptophan 2,3-Dioxygenase.
Year : 2019
Volume : 62
Issue : 20
First Page : 9161
Last Page : 9174
Authors : Yang D, Zhang S, Fang X, Guo L, Hu N, Guo Z, Li X, Yang S, He JC, Kuang C, Yang Q.
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.
|
Inhibition of human TDO transfected in HEK293 cells assessed as reduction in kynurenine production using L-tryptophan as substrate incubated for 12 hrs
|
Homo sapiens
|
260.0
nM
|
|
Journal : J Med Chem
Title : N-Benzyl/Aryl Substituted Tryptanthrin as Dual Inhibitors of Indoleamine 2,3-Dioxygenase and Tryptophan 2,3-Dioxygenase.
Year : 2019
Volume : 62
Issue : 20
First Page : 9161
Last Page : 9174
Authors : Yang D, Zhang S, Fang X, Guo L, Hu N, Guo Z, Li X, Yang S, He JC, Kuang C, Yang Q.
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.
|
Inhibition of N-terminal His-tagged human IDO1 expressed in Escherichia coli assessed as reduction in conversion of D-tryptophan to N-formyl kynurenine by methylene blue dye assay
|
Homo sapiens
|
71.8
nM
|
|
Journal : J Med Chem
Title : N-Benzyl/Aryl Substituted Tryptanthrin as Dual Inhibitors of Indoleamine 2,3-Dioxygenase and Tryptophan 2,3-Dioxygenase.
Year : 2019
Volume : 62
Issue : 20
First Page : 9161
Last Page : 9174
Authors : Yang D, Zhang S, Fang X, Guo L, Hu N, Guo Z, Li X, Yang S, He JC, Kuang C, Yang Q.
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.
|
Inhibition of IFN-gamma stimulated IDO1 in human HeLa cells assessed as reduction in formation of kynurenine incubated for 48 hrs in presence of IFNgamma by microplate reader assay
|
Homo sapiens
|
7.1
nM
|
|
Journal : J Med Chem
Title : N-Benzyl/Aryl Substituted Tryptanthrin as Dual Inhibitors of Indoleamine 2,3-Dioxygenase and Tryptophan 2,3-Dioxygenase.
Year : 2019
Volume : 62
Issue : 20
First Page : 9161
Last Page : 9174
Authors : Yang D, Zhang S, Fang X, Guo L, Hu N, Guo Z, Li X, Yang S, He JC, Kuang C, Yang Q.
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.
|
Inhibition of IDO1 in IFNgamma-stimulated human A375 cells assessed as reduction in L-Kyn level measured after 48 hrs by HPLC analysis
|
Homo sapiens
|
7.7
nM
|
|
Journal : J Med Chem
Title : Discovery of Highly Potent Benzimidazole Derivatives as Indoleamine 2,3-Dioxygenase-1 (IDO1) Inhibitors: From Structure-Based Virtual Screening to in Vivo Pharmacodynamic Activity.
Year : 2020
Volume : 63
Issue : 6
First Page : 3047
Last Page : 3065
Authors : Serafini M, Torre E, Aprile S, Grosso ED, Gesù A, Griglio A, Colombo G, Travelli C, Paiella S, Adamo A, Orecchini E, Coletti A, Pallotta MT, Ugel S, Massarotti A, Pirali T, Fallarini S.
Abstract : In this study, a successful medicinal chemistry campaign that exploited virtual, biophysical, and biological investigations led to the identification of a novel class of IDO1 inhibitors based on a benzimidazole substructure. This family of compounds is endowed with an extensive bonding network in the protein active site, including the interaction with pocket C, a region not commonly exploited by previously reported IDO1 inhibitors. The tight packing of selected compounds within the enzyme contributes to the strong binding interaction with IDO1, to the inhibitory potency at the low nanomolar level in several tumoral settings, and to the selectivity toward IDO1 over TDO and CYPs. Notably, a significant reduction of L-Kyn levels in plasma, together with a potent effect on abrogating immunosuppressive properties of MDSC-like cells isolated from patients affected by pancreatic ductal adenocarcinoma, was observed, pointing to this class of molecules as a valuable template for boosting the antitumor immune system.
|
Inhibition of IDO1 in IFNgamma-stimulated human A375 cells assessed as reduction in L-Kyn level at 1 uM measured after 48 hrs by HPLC analysis relative to control
|
Homo sapiens
|
92.0
%
|
|
Journal : J Med Chem
Title : Discovery of Highly Potent Benzimidazole Derivatives as Indoleamine 2,3-Dioxygenase-1 (IDO1) Inhibitors: From Structure-Based Virtual Screening to in Vivo Pharmacodynamic Activity.
Year : 2020
Volume : 63
Issue : 6
First Page : 3047
Last Page : 3065
Authors : Serafini M, Torre E, Aprile S, Grosso ED, Gesù A, Griglio A, Colombo G, Travelli C, Paiella S, Adamo A, Orecchini E, Coletti A, Pallotta MT, Ugel S, Massarotti A, Pirali T, Fallarini S.
Abstract : In this study, a successful medicinal chemistry campaign that exploited virtual, biophysical, and biological investigations led to the identification of a novel class of IDO1 inhibitors based on a benzimidazole substructure. This family of compounds is endowed with an extensive bonding network in the protein active site, including the interaction with pocket C, a region not commonly exploited by previously reported IDO1 inhibitors. The tight packing of selected compounds within the enzyme contributes to the strong binding interaction with IDO1, to the inhibitory potency at the low nanomolar level in several tumoral settings, and to the selectivity toward IDO1 over TDO and CYPs. Notably, a significant reduction of L-Kyn levels in plasma, together with a potent effect on abrogating immunosuppressive properties of MDSC-like cells isolated from patients affected by pancreatic ductal adenocarcinoma, was observed, pointing to this class of molecules as a valuable template for boosting the antitumor immune system.
|
Inhibition of human IDO1 expressed in Escherichia coli using L-tryptophan as substrate after 1 hr by UV absorption analysis
|
Homo sapiens
|
67.0
nM
|
|
Journal : Bioorg Med Chem
Title : 4,6-Substituted-1H-Indazoles as potent IDO1/TDO dual inhibitors.
Year : 2019
Volume : 27
Issue : 6
First Page : 1087
Last Page : 1098
Authors : Yang L, Chen Y, He J, Njoya EM, Chen J, Liu S, Xie C, Huang W, Wang F, Wang Z, Li Y, Qian S.
Abstract : Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO) are constitutively overexpressed in many types of cancer cells and exert important immunosuppressive functions. In this article, a series of 4,6-substituted-1H-indazole derivatives were synthesized and evaluated the inhibitory activities against IDO1 and TDO, as well as their structure-activity relationships (SARs). Among these, compound 35 displayed the most IDO1 inhibitory potency with an IC<sub>50</sub> value of 0.74 μM in an enzymatic assay and 1.37 μM in HeLa cells. Quantitative analysis of the Western blot results indicated that 35 significantly decreased the INFγ-induced IDO1 expression in a concentration-dependent manner. In addition, 35 showed promising TDO inhibition with an IC<sub>50</sub> value of 2.93 μM in the enzymatic assay and 7.54 μM in A172 cells. Moreover, compound 35 exhibited in vivo antitumor activity in the CT26 xenograft model. These findings suggest that 1H-indazole derivative 35 is a potent IDO1/TDO dual inhibitor, and has the potential to be developed for IDO1/TDO-related cancer treatment.
|
Inhibition of human IDO1
|
Homo sapiens
|
72.0
nM
|
|
Journal : Bioorg Med Chem
Title : 4,6-Substituted-1H-Indazoles as potent IDO1/TDO dual inhibitors.
Year : 2019
Volume : 27
Issue : 6
First Page : 1087
Last Page : 1098
Authors : Yang L, Chen Y, He J, Njoya EM, Chen J, Liu S, Xie C, Huang W, Wang F, Wang Z, Li Y, Qian S.
Abstract : Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO) are constitutively overexpressed in many types of cancer cells and exert important immunosuppressive functions. In this article, a series of 4,6-substituted-1H-indazole derivatives were synthesized and evaluated the inhibitory activities against IDO1 and TDO, as well as their structure-activity relationships (SARs). Among these, compound 35 displayed the most IDO1 inhibitory potency with an IC<sub>50</sub> value of 0.74 μM in an enzymatic assay and 1.37 μM in HeLa cells. Quantitative analysis of the Western blot results indicated that 35 significantly decreased the INFγ-induced IDO1 expression in a concentration-dependent manner. In addition, 35 showed promising TDO inhibition with an IC<sub>50</sub> value of 2.93 μM in the enzymatic assay and 7.54 μM in A172 cells. Moreover, compound 35 exhibited in vivo antitumor activity in the CT26 xenograft model. These findings suggest that 1H-indazole derivative 35 is a potent IDO1/TDO dual inhibitor, and has the potential to be developed for IDO1/TDO-related cancer treatment.
|
Inhibition of TDO in human U87 MG cells using L-Trp as substrate after 8 hrs
|
Homo sapiens
|
260.0
nM
|
|
Journal : Eur J Med Chem
Title : Tryptophan 2,3-dioxygenase inhibitory activities of tryptanthrin derivatives.
Year : 2018
Volume : 160
First Page : 133
Last Page : 145
Authors : Zhang S, Qi F, Fang X, Yang D, Hu H, Huang Q, Kuang C, Yang Q.
Abstract : Tryptophan 2,3-dioxygenase (TDO) is becoming a promising therapeutic target due to its involvement in cancer and neurodegenerative diseases. Development of efficient TDO inhibitors is a prime strategy in disease treatment. However, the lack of a TDO inhibitor bioassay system slows the progress of TDO inhibitor research. Herein, an active recombinant human TDO (hTDO) was prepared under optimal expression conditions, an enzymatic assay was optimized, and two cellular assays of TDO activity were developed. Then, the potential TDO inhibitory activities of nine tryptanthrin derivatives (5a-5i) were evaluated, and the inhibitory constants (Ki), enzymatic and cellular half maximal inhibitory concentrations (IC<sub>50</sub>) were measured, and the type of inhibition was determined. The tryptanthrins had various levels of TDO inhibitory activities; tryptanthrins with a substituent at 8-position had stronger inhibitory activities than the other derivatives. Moreover, most of the compounds, except 5g and 5h, exhibited better inhibitory activities than the previously reported TDO inhibitor LM10. Furthermore, the molecular docking study of compounds 5c and 5d revealed that the O atom of the tryptanthrin ring is directed toward the heme iron (Fe) of hTDO via strong coordination interactions. These findings suggest that tryptanthrin and its derivatives have the potential to be developed as promising molecules for TDO-related target therapy.
|
Inhibition of TDO (unknown origin) expressed in HEK293 cells using L-Trp as substrate after 8 hrs
|
Homo sapiens
|
242.0
nM
|
|
Journal : Eur J Med Chem
Title : Tryptophan 2,3-dioxygenase inhibitory activities of tryptanthrin derivatives.
Year : 2018
Volume : 160
First Page : 133
Last Page : 145
Authors : Zhang S, Qi F, Fang X, Yang D, Hu H, Huang Q, Kuang C, Yang Q.
Abstract : Tryptophan 2,3-dioxygenase (TDO) is becoming a promising therapeutic target due to its involvement in cancer and neurodegenerative diseases. Development of efficient TDO inhibitors is a prime strategy in disease treatment. However, the lack of a TDO inhibitor bioassay system slows the progress of TDO inhibitor research. Herein, an active recombinant human TDO (hTDO) was prepared under optimal expression conditions, an enzymatic assay was optimized, and two cellular assays of TDO activity were developed. Then, the potential TDO inhibitory activities of nine tryptanthrin derivatives (5a-5i) were evaluated, and the inhibitory constants (Ki), enzymatic and cellular half maximal inhibitory concentrations (IC<sub>50</sub>) were measured, and the type of inhibition was determined. The tryptanthrins had various levels of TDO inhibitory activities; tryptanthrins with a substituent at 8-position had stronger inhibitory activities than the other derivatives. Moreover, most of the compounds, except 5g and 5h, exhibited better inhibitory activities than the previously reported TDO inhibitor LM10. Furthermore, the molecular docking study of compounds 5c and 5d revealed that the O atom of the tryptanthrin ring is directed toward the heme iron (Fe) of hTDO via strong coordination interactions. These findings suggest that tryptanthrin and its derivatives have the potential to be developed as promising molecules for TDO-related target therapy.
|
Inhibition of IDO1 in human HeLa cells using L-tryptophan as substrate incubated for 48 hrs
|
Homo sapiens
|
10.0
nM
|
|
Journal : Eur J Med Chem
Title : Discovery of phosphonamidate IDO1 inhibitors for the treatment of non-small cell lung cancer.
Year : 2019
Volume : 182
First Page : 111629
Last Page : 111629
Authors : Du Q, Feng X, Wang Y, Xu X, Zhang Y, Qu X, Li Z, Bian J.
Abstract : Targeting indoleamine 2,3-dioxygenase 1 (IDO1) has been identified as an attractive approach for the development of cancer immunotherapy. In this study, a series of phosphonamidate ester containing compounds were designed, synthesized and evaluated for their inhibitory activities against IDO1. Among them, compounds 16, 17, and 26 with good IDO1 inhibitory (HeLa IDO1 IC<sub>50</sub> = 10-21 nM, hIDO1 IC<sub>50</sub> = 78-121 nM) activities were selected for further investigation and showed good physicochemical properties. Furthermore, based on comparable PK profile and excellent IDO2/TDO inhibitory potency, representative compound 16 was selected for further bio-evaluation and characterized with good efficacy in suppressing lung metastasis (77% inhibition rate) of Lewis cells in vivo. Thus, compound 16 could be a potential and efficacious agent for further evaluation.
|
Inhibition of recombinant N-terminal His-tagged human IDO1 expressed in Escherichia coli assessed as reduction in N-formylkynurenine formation using L-tryptophan as substrate
|
Homo sapiens
|
72.0
nM
|
|
Journal : Eur J Med Chem
Title : Discovery of phosphonamidate IDO1 inhibitors for the treatment of non-small cell lung cancer.
Year : 2019
Volume : 182
First Page : 111629
Last Page : 111629
Authors : Du Q, Feng X, Wang Y, Xu X, Zhang Y, Qu X, Li Z, Bian J.
Abstract : Targeting indoleamine 2,3-dioxygenase 1 (IDO1) has been identified as an attractive approach for the development of cancer immunotherapy. In this study, a series of phosphonamidate ester containing compounds were designed, synthesized and evaluated for their inhibitory activities against IDO1. Among them, compounds 16, 17, and 26 with good IDO1 inhibitory (HeLa IDO1 IC<sub>50</sub> = 10-21 nM, hIDO1 IC<sub>50</sub> = 78-121 nM) activities were selected for further investigation and showed good physicochemical properties. Furthermore, based on comparable PK profile and excellent IDO2/TDO inhibitory potency, representative compound 16 was selected for further bio-evaluation and characterized with good efficacy in suppressing lung metastasis (77% inhibition rate) of Lewis cells in vivo. Thus, compound 16 could be a potential and efficacious agent for further evaluation.
|
Inhibition of N-terminal His-tagged human IDO2 expressed in Escherichia coli expression system
|
Homo sapiens
|
710.0
nM
|
|
Journal : Eur J Med Chem
Title : Discovery of phosphonamidate IDO1 inhibitors for the treatment of non-small cell lung cancer.
Year : 2019
Volume : 182
First Page : 111629
Last Page : 111629
Authors : Du Q, Feng X, Wang Y, Xu X, Zhang Y, Qu X, Li Z, Bian J.
Abstract : Targeting indoleamine 2,3-dioxygenase 1 (IDO1) has been identified as an attractive approach for the development of cancer immunotherapy. In this study, a series of phosphonamidate ester containing compounds were designed, synthesized and evaluated for their inhibitory activities against IDO1. Among them, compounds 16, 17, and 26 with good IDO1 inhibitory (HeLa IDO1 IC<sub>50</sub> = 10-21 nM, hIDO1 IC<sub>50</sub> = 78-121 nM) activities were selected for further investigation and showed good physicochemical properties. Furthermore, based on comparable PK profile and excellent IDO2/TDO inhibitory potency, representative compound 16 was selected for further bio-evaluation and characterized with good efficacy in suppressing lung metastasis (77% inhibition rate) of Lewis cells in vivo. Thus, compound 16 could be a potential and efficacious agent for further evaluation.
|
Antimetastatic activity against LLC cells allografted in C57BL6 mouse assessed as inhibition of metastatic nodules in lung at 60 mg/kg, ig after 30 days by H and E staining based analysis relative to control
|
Mus musculus
|
77.0
%
|
|
Journal : Eur J Med Chem
Title : Discovery of phosphonamidate IDO1 inhibitors for the treatment of non-small cell lung cancer.
Year : 2019
Volume : 182
First Page : 111629
Last Page : 111629
Authors : Du Q, Feng X, Wang Y, Xu X, Zhang Y, Qu X, Li Z, Bian J.
Abstract : Targeting indoleamine 2,3-dioxygenase 1 (IDO1) has been identified as an attractive approach for the development of cancer immunotherapy. In this study, a series of phosphonamidate ester containing compounds were designed, synthesized and evaluated for their inhibitory activities against IDO1. Among them, compounds 16, 17, and 26 with good IDO1 inhibitory (HeLa IDO1 IC<sub>50</sub> = 10-21 nM, hIDO1 IC<sub>50</sub> = 78-121 nM) activities were selected for further investigation and showed good physicochemical properties. Furthermore, based on comparable PK profile and excellent IDO2/TDO inhibitory potency, representative compound 16 was selected for further bio-evaluation and characterized with good efficacy in suppressing lung metastasis (77% inhibition rate) of Lewis cells in vivo. Thus, compound 16 could be a potential and efficacious agent for further evaluation.
|
Inhibition of IFN-gamma-induced human TDO2 transfected in HeLa cells at 10 times IDO1 IC50 concentration using L-tryptophan as substrate incubated for 24 hrs relative to control
|
Homo sapiens
|
20.0
%
|
|
Journal : Eur J Med Chem
Title : Effective Virtual Screening Strategy toward heme-containing proteins: Identification of novel IDO1 inhibitors.
Year : 2019
Volume : 184
First Page : 111750
Last Page : 111750
Authors : Zou Y, Hu Y, Ge S, Zheng Y, Li Y, Liu W, Guo W, Zhang Y, Xu Q, Lai Y.
Abstract : Developing small molecules occupying the heme-binding site using computational approaches remains a challenging task because it is difficult to characterize heme-ligand interaction in heme-containing protein. Indoleamine 2,3-dioxygenase 1 (IDO1) is an intracellular heme-containing dioxygenase which is associated with the immunosuppressive effects in cancer. With IDO1 as an example, herein we report a combined virtual screening (VS) strategy including high-specificity heme-binding group (HmBG)-based pharmacophore screening and cascade molecular docking to identify novel IDO1 inhibitors. A total of four hit compounds were obtained and showed proper binding with the heme iron coordinating site. Further structural optimization led to a promising compound S18-3, which exerted potent anti-tumor efficacy in BALB/c mice bearing established CT26 tumors by activating the host's immune system. These results suggest that S18-3 merits further study to assess its potential for the intervention of cancer. Furthermore, our study also unveils a novel in silico-based strategy for identifying potential regulators for hemeproteins within short timeframe.
|
Inhibition of IDO1 in IFN-gamma stimulated human HeLa cells assessed as reduction in kynurenine production using L-tryptophan as substrate incubated for 24 hrs
|
Homo sapiens
|
16.0
nM
|
|
Journal : Eur J Med Chem
Title : Effective Virtual Screening Strategy toward heme-containing proteins: Identification of novel IDO1 inhibitors.
Year : 2019
Volume : 184
First Page : 111750
Last Page : 111750
Authors : Zou Y, Hu Y, Ge S, Zheng Y, Li Y, Liu W, Guo W, Zhang Y, Xu Q, Lai Y.
Abstract : Developing small molecules occupying the heme-binding site using computational approaches remains a challenging task because it is difficult to characterize heme-ligand interaction in heme-containing protein. Indoleamine 2,3-dioxygenase 1 (IDO1) is an intracellular heme-containing dioxygenase which is associated with the immunosuppressive effects in cancer. With IDO1 as an example, herein we report a combined virtual screening (VS) strategy including high-specificity heme-binding group (HmBG)-based pharmacophore screening and cascade molecular docking to identify novel IDO1 inhibitors. A total of four hit compounds were obtained and showed proper binding with the heme iron coordinating site. Further structural optimization led to a promising compound S18-3, which exerted potent anti-tumor efficacy in BALB/c mice bearing established CT26 tumors by activating the host's immune system. These results suggest that S18-3 merits further study to assess its potential for the intervention of cancer. Furthermore, our study also unveils a novel in silico-based strategy for identifying potential regulators for hemeproteins within short timeframe.
|
Inhibition of IDO1 in IFN-gamma stimulated human HeLa cells assessed as reduction in kynurenine production at 30 uM using L-tryptophan as substrate incubated for 24 hrs relative to control
|
Homo sapiens
|
97.0
%
|
|
Journal : Eur J Med Chem
Title : Effective Virtual Screening Strategy toward heme-containing proteins: Identification of novel IDO1 inhibitors.
Year : 2019
Volume : 184
First Page : 111750
Last Page : 111750
Authors : Zou Y, Hu Y, Ge S, Zheng Y, Li Y, Liu W, Guo W, Zhang Y, Xu Q, Lai Y.
Abstract : Developing small molecules occupying the heme-binding site using computational approaches remains a challenging task because it is difficult to characterize heme-ligand interaction in heme-containing protein. Indoleamine 2,3-dioxygenase 1 (IDO1) is an intracellular heme-containing dioxygenase which is associated with the immunosuppressive effects in cancer. With IDO1 as an example, herein we report a combined virtual screening (VS) strategy including high-specificity heme-binding group (HmBG)-based pharmacophore screening and cascade molecular docking to identify novel IDO1 inhibitors. A total of four hit compounds were obtained and showed proper binding with the heme iron coordinating site. Further structural optimization led to a promising compound S18-3, which exerted potent anti-tumor efficacy in BALB/c mice bearing established CT26 tumors by activating the host's immune system. These results suggest that S18-3 merits further study to assess its potential for the intervention of cancer. Furthermore, our study also unveils a novel in silico-based strategy for identifying potential regulators for hemeproteins within short timeframe.
|
Inhibition of IDO1 in IFN-gamma stimulated human HeLa cells assessed as reduction in kynurenine production at 1 uM incubated for 24 hrs relative to control
|
Homo sapiens
|
99.7
%
|
|
Journal : Bioorg Med Chem
Title : Design, synthesis and biological evaluation of 2,5-dimethylfuran-3-carboxylic acid derivatives as potential IDO1 inhibitors.
Year : 2019
Volume : 27
Issue : 8
First Page : 1605
Last Page : 1618
Authors : Yang X, Cai S, Liu X, Chen P, Zhou J, Zhang H.
Abstract : Indoleamine 2,3-dioxygenase 1 (IDO1) plays a vital role in tumor immune escape and has emerged as a promising target for cancer immunotherapy. In this study, a novel series of 2,5-dimethylfuran-3-carboxylic acid derivatives were designed, synthesized and evaluated for inhibitory activities against IDO1, and their structure-activity relationship was investigated. Among these, compound 19a exhibited excellent IDO1 inhibitory activity (HeLa cellular IC<sub>50</sub> = 4.0 nM, THP-1 cellular IC<sub>50</sub> = 4.6 nM). Further molecular docking studies revealed that the compound 19a formed a coordinate bond with the heme iron through the carboxylic acid moiety. These results indicate that compound 19a is a potential IDO1 inhibitor for further investigation.
|
Inhibition of IDO1 in IFN-gamma stimulated human HeLa cells assessed as reduction in kynurenine production incubated for 24 hrs relative to control
|
Homo sapiens
|
10.3
nM
|
|
Journal : Bioorg Med Chem
Title : Design, synthesis and biological evaluation of 2,5-dimethylfuran-3-carboxylic acid derivatives as potential IDO1 inhibitors.
Year : 2019
Volume : 27
Issue : 8
First Page : 1605
Last Page : 1618
Authors : Yang X, Cai S, Liu X, Chen P, Zhou J, Zhang H.
Abstract : Indoleamine 2,3-dioxygenase 1 (IDO1) plays a vital role in tumor immune escape and has emerged as a promising target for cancer immunotherapy. In this study, a novel series of 2,5-dimethylfuran-3-carboxylic acid derivatives were designed, synthesized and evaluated for inhibitory activities against IDO1, and their structure-activity relationship was investigated. Among these, compound 19a exhibited excellent IDO1 inhibitory activity (HeLa cellular IC<sub>50</sub> = 4.0 nM, THP-1 cellular IC<sub>50</sub> = 4.6 nM). Further molecular docking studies revealed that the compound 19a formed a coordinate bond with the heme iron through the carboxylic acid moiety. These results indicate that compound 19a is a potential IDO1 inhibitor for further investigation.
|
Inhibition of IDO1 in IFN-gamma/LPS stimulated human THP-1 cells assessed as reduction in kynurenine production after 24 hrs
|
Homo sapiens
|
5.6
nM
|
|
Journal : Bioorg Med Chem
Title : Design, synthesis and biological evaluation of 2,5-dimethylfuran-3-carboxylic acid derivatives as potential IDO1 inhibitors.
Year : 2019
Volume : 27
Issue : 8
First Page : 1605
Last Page : 1618
Authors : Yang X, Cai S, Liu X, Chen P, Zhou J, Zhang H.
Abstract : Indoleamine 2,3-dioxygenase 1 (IDO1) plays a vital role in tumor immune escape and has emerged as a promising target for cancer immunotherapy. In this study, a novel series of 2,5-dimethylfuran-3-carboxylic acid derivatives were designed, synthesized and evaluated for inhibitory activities against IDO1, and their structure-activity relationship was investigated. Among these, compound 19a exhibited excellent IDO1 inhibitory activity (HeLa cellular IC<sub>50</sub> = 4.0 nM, THP-1 cellular IC<sub>50</sub> = 4.6 nM). Further molecular docking studies revealed that the compound 19a formed a coordinate bond with the heme iron through the carboxylic acid moiety. These results indicate that compound 19a is a potential IDO1 inhibitor for further investigation.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
13.32
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
-1.456
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.01
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.0
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.01
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.0
%
|
|
Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.
|
Inhibition of recombinant human IDO1 expressed in Escherichia coli at 10 uM relative to control
|
Homo sapiens
|
97.59
%
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of 5-(pyridin-3-yl)-1H-indole-4,7-diones as indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors.
Year : 2020
Volume : 30
Issue : 4
First Page : 126901
Last Page : 126901
Authors : Kong KM, Zhang JW, Liu BZ, Meng GR, Zhang Q.
Abstract : Early studies demonstrated that over expression of indoleamine 2,3-dioxygenase (IDO1) in tumor microenvironment results in tumor immune escape. Herein, in order to simplify the structure of two kinds of IDO1 inhibitors from marine alkaloid, Exiguamine A and Tsitsikammamines, we designed, synthesized a series of 1H-indole-4,7-dione derivatives and evaluated their inhibitory activity in IDO1 enzyme and in IFN-γ stimulated Hela cells in vitro. The structure-activity relationship demonstrated that 5-(pyridin-3-yl)-1H-indole-4,7-dione is a promising scaffold for IDO1 inhibitors and most compounds with this core showed moderate inhibition potency at micromole level. Our further enzyme kinetics experiments reveal that these new developed compounds might act as reversible competitive inhibitors of IDO1.
|
Inhibition of recombinant human IDO1 expressed in Escherichia coli
|
Homo sapiens
|
97.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of 5-(pyridin-3-yl)-1H-indole-4,7-diones as indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors.
Year : 2020
Volume : 30
Issue : 4
First Page : 126901
Last Page : 126901
Authors : Kong KM, Zhang JW, Liu BZ, Meng GR, Zhang Q.
Abstract : Early studies demonstrated that over expression of indoleamine 2,3-dioxygenase (IDO1) in tumor microenvironment results in tumor immune escape. Herein, in order to simplify the structure of two kinds of IDO1 inhibitors from marine alkaloid, Exiguamine A and Tsitsikammamines, we designed, synthesized a series of 1H-indole-4,7-dione derivatives and evaluated their inhibitory activity in IDO1 enzyme and in IFN-γ stimulated Hela cells in vitro. The structure-activity relationship demonstrated that 5-(pyridin-3-yl)-1H-indole-4,7-dione is a promising scaffold for IDO1 inhibitors and most compounds with this core showed moderate inhibition potency at micromole level. Our further enzyme kinetics experiments reveal that these new developed compounds might act as reversible competitive inhibitors of IDO1.
|
Inhibition of IFNgamma-stimulated IDO1 in human HeLa cells
|
Homo sapiens
|
13.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of 5-(pyridin-3-yl)-1H-indole-4,7-diones as indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors.
Year : 2020
Volume : 30
Issue : 4
First Page : 126901
Last Page : 126901
Authors : Kong KM, Zhang JW, Liu BZ, Meng GR, Zhang Q.
Abstract : Early studies demonstrated that over expression of indoleamine 2,3-dioxygenase (IDO1) in tumor microenvironment results in tumor immune escape. Herein, in order to simplify the structure of two kinds of IDO1 inhibitors from marine alkaloid, Exiguamine A and Tsitsikammamines, we designed, synthesized a series of 1H-indole-4,7-dione derivatives and evaluated their inhibitory activity in IDO1 enzyme and in IFN-γ stimulated Hela cells in vitro. The structure-activity relationship demonstrated that 5-(pyridin-3-yl)-1H-indole-4,7-dione is a promising scaffold for IDO1 inhibitors and most compounds with this core showed moderate inhibition potency at micromole level. Our further enzyme kinetics experiments reveal that these new developed compounds might act as reversible competitive inhibitors of IDO1.
|
Inhibition of IDO1 (unknown origin)
|
Homo sapiens
|
90.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Synthesis of novel tryptanthrin derivatives as dual inhibitors of indoleamine 2,3-dioxygenase 1 and tryptophan 2,3-dioxygenase.
Year : 2020
Volume : 30
Issue : 11
First Page : 127159
Last Page : 127159
Authors : Li Y, Zhang S, Wang R, Cui M, Liu W, Yang Q, Kuang C.
Abstract : Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO) are promising drug development targets due to their implications in pathologies such as cancer and neurodegenerative diseases. The search for IDO1 inhibitor has been intensely pursued but there is a paucity of potent TDO and IDO1/TDO dual inhibitors. Natural product tryptanthrin has been confirmed to bear IDO1 and/or TDO inhibitory activities. Herein, twelve novel tryptanthrin derivatives were synthesized and evaluated for the IDO1 and TDO inhibitory potency. All of the compounds were found to be IDO1/TDO dual inhibitors, in particular, compound 9a and 9b bore IDO1 inhibitory activity similar to that of INCB024360, and compound 5a and 9b had remarkable TDO inhibitory activity superior to that of the well-known TDO inhibitor LM10. This work enriches the collection of IDO1/TDO dual inhibitors and provides chemical molecules for potential development into drugs.
|
Inhibition of IDO1 in human HeLa cells
|
Homo sapiens
|
20.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Synthesis of novel tryptanthrin derivatives as dual inhibitors of indoleamine 2,3-dioxygenase 1 and tryptophan 2,3-dioxygenase.
Year : 2020
Volume : 30
Issue : 11
First Page : 127159
Last Page : 127159
Authors : Li Y, Zhang S, Wang R, Cui M, Liu W, Yang Q, Kuang C.
Abstract : Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO) are promising drug development targets due to their implications in pathologies such as cancer and neurodegenerative diseases. The search for IDO1 inhibitor has been intensely pursued but there is a paucity of potent TDO and IDO1/TDO dual inhibitors. Natural product tryptanthrin has been confirmed to bear IDO1 and/or TDO inhibitory activities. Herein, twelve novel tryptanthrin derivatives were synthesized and evaluated for the IDO1 and TDO inhibitory potency. All of the compounds were found to be IDO1/TDO dual inhibitors, in particular, compound 9a and 9b bore IDO1 inhibitory activity similar to that of INCB024360, and compound 5a and 9b had remarkable TDO inhibitory activity superior to that of the well-known TDO inhibitor LM10. This work enriches the collection of IDO1/TDO dual inhibitors and provides chemical molecules for potential development into drugs.
|
Inhibition of IDO1 in IFN-gamma stimulated human HeLa cells using L-tryptophan as substrate incubated for 48 hrs by fluorescence assay
|
Homo sapiens
|
12.5
nM
|
|
Journal : ACS Med Chem Lett
Title : Discovery of Potent and Orally Available Bicyclo[1.1.1]pentane-Derived Indoleamine-2,3-dioxygenase 1 (IDO1) Inhibitors.
Year : 2020
Volume : 11
Issue : 8
First Page : 1548
Last Page : 1554
Authors : Pu Q, Zhang H, Guo L, Cheng M, Doty AC, Ferguson H, Fradera X, Lesburg CA, McGowan MA, Miller JR, Geda P, Song X, Otte K, Sciammetta N, Solban N, Yu W, Sloman DL, Zhou H, Lammens A, Neumann L, Bennett DJ, Pasternak A, Han Y.
Abstract : Indoleamine-2,3-dioxygenase 1 (IDO1) inhibition and its combination with immune checkpoint inhibitors like <i>pembrolizumab</i> have drawn considerable attention from both academia and the pharmaceutical industry. Here, we describe the discovery of a novel class of highly potent IDO1 heme-displacing inhibitors featuring a unique bicyclo[1.1.1]pentane motif. Compound <b>1</b>, evolving from an ALIS (automated ligand identification system) hit, exhibited excellent potency but lacked the desired pharmacokinetic profile due to extensive amide hydrolysis of the benzamide moiety. Replacing the central phenyl ring in <b>1</b> with a bicyclo[1.1.1]pentane bioisostere effectively circumvented the amide hydrolysis issue, resulting in the discovery of compound <b>2</b> with a favorable overall profile such as excellent potency, selectivity, pharmacokinetics, and a low predicted human dose.
|
Inhibition of IDO1 (unknown origin) assessed as reduction in kynurenine formation using L-tryptophan as substrate incubated for 60 mins by fluorescence based assay
|
Homo sapiens
|
66.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of novel hydroxyamidine derivatives as indoleamine 2,3-dioxygenase 1 inhibitors with in vivo anti-tumor efficacy.
Year : 2020
Volume : 30
Issue : 8
First Page : 127038
Last Page : 127038
Authors : Liu C, Nan Y, Xia Z, Gu K, Chen C, Dong X, Ju D, Zhao W.
Abstract : Indoleamine 2,3-dioxygenase 1 (IDO1) is closely associated with immune escape in many tumor tissues, and is considered to be a valuable therapeutic target in cancer immunotherapy. In this study, the modification of amino sidechain was performed with the hydroxyamidine core kept intact to optimize lead compound Epacadostat. 19 new compounds with hydrazide, thietane or sulfonamide moiety as polar capping group in sidechain were prepared and their IDO1 inhibitory activities were evaluated. Sulfonamide 3a showed potent IDO1 inhibition in both enzymatic and cellular assays with the IC<sub>50</sub> value of 71 nM and EC<sub>50</sub> value of 11 nM, respectively. Furthermore, in vivo Lewis lung cancer (LLC) allograft studies of 3a indicated that it handicapped the tumor growth with similar efficacy to Epacadostat. Molecular docking demonstrated that the change of polar capping group affords influence on the orientation of amino ethylene side chain and forms new hydrogen bonding.
|
Inhibition of IDO1 in IFN-gamma stimulated human HeLa cells assessed as reduction in kynurenine formation using L-tryptophan as substrate incubated for 24 hrs by UV-spectrophotometry
|
Homo sapiens
|
8.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of novel hydroxyamidine derivatives as indoleamine 2,3-dioxygenase 1 inhibitors with in vivo anti-tumor efficacy.
Year : 2020
Volume : 30
Issue : 8
First Page : 127038
Last Page : 127038
Authors : Liu C, Nan Y, Xia Z, Gu K, Chen C, Dong X, Ju D, Zhao W.
Abstract : Indoleamine 2,3-dioxygenase 1 (IDO1) is closely associated with immune escape in many tumor tissues, and is considered to be a valuable therapeutic target in cancer immunotherapy. In this study, the modification of amino sidechain was performed with the hydroxyamidine core kept intact to optimize lead compound Epacadostat. 19 new compounds with hydrazide, thietane or sulfonamide moiety as polar capping group in sidechain were prepared and their IDO1 inhibitory activities were evaluated. Sulfonamide 3a showed potent IDO1 inhibition in both enzymatic and cellular assays with the IC<sub>50</sub> value of 71 nM and EC<sub>50</sub> value of 11 nM, respectively. Furthermore, in vivo Lewis lung cancer (LLC) allograft studies of 3a indicated that it handicapped the tumor growth with similar efficacy to Epacadostat. Molecular docking demonstrated that the change of polar capping group affords influence on the orientation of amino ethylene side chain and forms new hydrogen bonding.
|
Inhibition of IDO1 in IFNgamma-stimulated human HeLa cells using L-tryptophan as substrate measured after 48 hrs
|
Homo sapiens
|
5.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Discovery of Hydroxyamidine Derivatives as Highly Potent, Selective Indoleamine-2,3-dioxygenase 1 Inhibitors.
Year : 2021
Volume : 12
Issue : 2
First Page : 195
Last Page : 201
Authors : Jin F,Hu Q,Fei H,Lv H,Wang S,Gui B,Zhang J,Tu W,Zhang Y,Zhang L,Wan H,Zhang L,Hu B,Yang F,Bai C,He F,Zhang L,Tao W
Abstract : In this study, a series of novel hydroxyamidine derivatives were identified as potent and selective IDO1 inhibitors by structure-based drug design. Among them, compounds 13-15 and 18 exhibited favorable enzymatic and cellular activities. Compound 18 showed improved bioavailability in mouse, rat, and dog (F% = 44%, 58.8%, 102.1%, respectively). With reasonable in vivo pharmacokinetic properties, compound 18 was further evaluated in a transgenic MC38 xenograft mouse model. The combination of compound 18 with PD-1 monoclonal antibody showed a synergistic antitumor effect. These data indicated that compound 18 as a potential cancer immunotherapy agent should warrant further investigation.
|
Inhibition of human IDO1 expressed in Escherichia coli Rosetta using tryptophan as substrate incubated for 1 hr by methylene blue based assay
|
Homo sapiens
|
26.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Discovery of Hydroxyamidine Derivatives as Highly Potent, Selective Indoleamine-2,3-dioxygenase 1 Inhibitors.
Year : 2021
Volume : 12
Issue : 2
First Page : 195
Last Page : 201
Authors : Jin F,Hu Q,Fei H,Lv H,Wang S,Gui B,Zhang J,Tu W,Zhang Y,Zhang L,Wan H,Zhang L,Hu B,Yang F,Bai C,He F,Zhang L,Tao W
Abstract : In this study, a series of novel hydroxyamidine derivatives were identified as potent and selective IDO1 inhibitors by structure-based drug design. Among them, compounds 13-15 and 18 exhibited favorable enzymatic and cellular activities. Compound 18 showed improved bioavailability in mouse, rat, and dog (F% = 44%, 58.8%, 102.1%, respectively). With reasonable in vivo pharmacokinetic properties, compound 18 was further evaluated in a transgenic MC38 xenograft mouse model. The combination of compound 18 with PD-1 monoclonal antibody showed a synergistic antitumor effect. These data indicated that compound 18 as a potential cancer immunotherapy agent should warrant further investigation.
|
In vivo inhibition of IDO1 in nu/nu mouse xenografted with human SK-OV-3 cells assessed as reduction in kynurenine level at 100 mg/kg, po qd by HPLC-MS/MS analysis relative to control
|
Mus musculus
|
54.0
%
|
|
Journal : ACS Med Chem Lett
Title : Discovery and Preclinical Evaluation of BMS-986242, a Potent, Selective Inhibitor of Indoleamine-2,3-dioxygenase 1.
Year : 2021
Volume : 12
Issue : 2
First Page : 288
Last Page : 294
Authors : Cherney EC,Zhang L,Nara S,Zhu X,Gullo-Brown J,Maley D,Lin TA,Hunt JT,Huang C,Yang Z,Darienzo C,Discenza L,Ranasinghe A,Grubb M,Ziemba T,Traeger SC,Li X,Johnston K,Kopcho L,Fereshteh M,Foster K,Stefanski K,Fargnoli J,Swanson J,Brown J,Delpy D,Seitz SP,Borzilleri R,Vite G,Balog A
Abstract : Indoleamine 2,3-dioxygenase 1 (IDO1) is a heme-containing dioxygenase enzyme implicated in cancer immune response. This account details the discovery of BMS-986242, a novel IDO1 inhibitor designed for the treatment of a variety of cancers including metastatic melanoma and renal cell carcinoma. Given the substantial interest around this target for cancer immunotherapy, we sought to identify a structurally differentiated clinical candidate that performs comparably to linrodostat (BMS-986205) in terms of both in vitro potency and in vivo pharmacodynamic effect in a mouse xenograft model. On the basis of its preclinical profile, BMS-986242 was selected as a candidate for clinical development.
|
Inhibition of recombinant human IDO1 assessed as reduction in kynurenine formation using L-tryptophan as substrate incubated for 45 mins by microplate reader assay
|
Homo sapiens
|
58.0
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and biological evaluation of indole-2-carboxylic acid derivatives as IDO1/TDO dual inhibitors.
Year : 2020
Volume : 188
First Page : 111985
Last Page : 111985
Authors : Cui G,Lai F,Wang X,Chen X,Xu B
Abstract : Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO) are involved in the key steps of tryptophan metabolism and are potential new targets for tumor immunotherapy. In this work, a variety of indole-2-carboxylic acid derivatives were synthesized, and their inhibitory activities against both enzymes along with structure-activity relationships were investigated. As a result, a number of 6-acetamido-indole-2-carboxylic acid derivatives were found to be potent dual inhibitors with IC values at low micromolar levels. Among them, compound 9o-1 was the most potent inhibitor with an IC value of 1.17 μM for IDO1, and 1.55 μM for TDO, respectively. In addition, a para-benzoquinone derivative 9p-O, resulted from the oxidation of compound 9p, was also identified and it showed strong inhibition against the two enzymes with IC values at the double digit nanomolar level. Using molecular docking and molecular dynamic simulations, we predicted the binding modes of this class of compounds within IDO1 and TDO binding pocket. The results provide insights for further structural optimization of this series of IDO1/TDO dual inhibitors.
|
Inhibition of human IDO1 expressed in HEK293T cells assessed as reduction in N-formylkynurenine production incubated for 12 hrs by microplate reader analysis
|
Homo sapiens
|
9.63
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis, and biological evaluation of 1,2,5-oxadiazole-3-carboximidamide derivatives as novel indoleamine-2,3-dioxygenase 1 inhibitors.
Year : 2020
Volume : 189
First Page : 112059
Last Page : 112059
Authors : Song X,Sun P,Wang J,Guo W,Wang Y,Meng LH,Liu H
Abstract : Indoleamine 2,3-dioxygenase 1 (IDO1) is the enzyme catalyzing the oxidative metabolism of tryptophan, which accounts for cancer immunosuppression in tumor microenvironment. Several compounds targeting IDO1 have been reported and epacadostat shows strong inhibitory activity against IDO1, which is further studied in clinic trails. However, its pharmacokinetic profiles are not satisfactory. The half-life of epacadostat is 2.4 h in human and dosage is 50 mg BID in the phase III clinic trial. To overcome the shortcomings of epacadostat, structure-based drug design was performed to improve the pharmacokinetic profiles via changing the metabolic pathway of epacadostat and to enhance anti-tumor potency. A novel series of 1,2,5-oxadiazole-3-carboximidamide derivatives bearing cycle in the side chain were designed, synthesized, and biologically evaluated for their anti-tumor activity. Most of them exhibited potent activity against hIDO1 in enzymatic assays and in HEK293T cells over-expressing hIDO1. Among them, compound 23, 25 and 26 showed significant inhibitory activity against hIDO1 (IC = 108.7, 178.1 and 139.1 nM respectively) and in HEK293T cells expressing hIDO1 (cellular IC = 19.88, 68.59 and 57.76 nM respectively). Moreover, compound 25 displayed improved PK property with longer half-life (t = 3.81 h in CD-1 mice) and better oral bioavailability (F = 33.6%) compared with epacadostat. In addition, compound 25 showed similar potency to inhibit the growth of CT-26 syngeneic xenograft compared to epacadostat, making it justifiable for further investigation.
|
Inhibition of recombinant human IDO1 assessed as reduction in kynurenine production using L-tryptophan as substrate incubated for 30 mins by microplate reader analysis
|
Homo sapiens
|
87.4
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis, and biological evaluation of 1,2,5-oxadiazole-3-carboximidamide derivatives as novel indoleamine-2,3-dioxygenase 1 inhibitors.
Year : 2020
Volume : 189
First Page : 112059
Last Page : 112059
Authors : Song X,Sun P,Wang J,Guo W,Wang Y,Meng LH,Liu H
Abstract : Indoleamine 2,3-dioxygenase 1 (IDO1) is the enzyme catalyzing the oxidative metabolism of tryptophan, which accounts for cancer immunosuppression in tumor microenvironment. Several compounds targeting IDO1 have been reported and epacadostat shows strong inhibitory activity against IDO1, which is further studied in clinic trails. However, its pharmacokinetic profiles are not satisfactory. The half-life of epacadostat is 2.4 h in human and dosage is 50 mg BID in the phase III clinic trial. To overcome the shortcomings of epacadostat, structure-based drug design was performed to improve the pharmacokinetic profiles via changing the metabolic pathway of epacadostat and to enhance anti-tumor potency. A novel series of 1,2,5-oxadiazole-3-carboximidamide derivatives bearing cycle in the side chain were designed, synthesized, and biologically evaluated for their anti-tumor activity. Most of them exhibited potent activity against hIDO1 in enzymatic assays and in HEK293T cells over-expressing hIDO1. Among them, compound 23, 25 and 26 showed significant inhibitory activity against hIDO1 (IC = 108.7, 178.1 and 139.1 nM respectively) and in HEK293T cells expressing hIDO1 (cellular IC = 19.88, 68.59 and 57.76 nM respectively). Moreover, compound 25 displayed improved PK property with longer half-life (t = 3.81 h in CD-1 mice) and better oral bioavailability (F = 33.6%) compared with epacadostat. In addition, compound 25 showed similar potency to inhibit the growth of CT-26 syngeneic xenograft compared to epacadostat, making it justifiable for further investigation.
|
Inhibition of IDO1 (unknown origin) assessed as reduction in L-kynurenine formation using L-tryptophan as substrate incubated for 30 mins by microplate spectrophotometry analysis
|
Homo sapiens
|
75.0
nM
|
|
Journal : Eur J Med Chem
Title : Discovery and structure-activity relationship studies of 1-aryl-1H-naphtho[2,3-d][1,2,3]triazole-4,9-dione derivatives as potent dual inhibitors of indoleamine 2,3-dioxygenase 1 (IDO1) and trytophan 2,3-dioxygenase (TDO).
Year : 2020
Volume : 207
First Page : 112703
Last Page : 112703
Authors : Pan S,Zhou Y,Wang Q,Wang Y,Tian C,Wang T,Huang L,Nan J,Li L,Yang S
Abstract : Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO), which mediate kynurenine pathway of tryptophan degradation, have emerged as potential new targets in immunotherapy for treatment of cancer because of their critical role in immunosuppression in the tumor microenvironment. In this investigation, we report the structural optimization and structure-activity relationship studies of 1-phenyl-1H-naphtho[2,3-d][1,2,3]triazole-4,9-dione derivatives as a new class of IDO1/TDO dual inhibitors. Among all the obtained dual inhibitors, 1-(3-chloro-4-fluorophenyl)-6-fluoro-1H-naphtho[2,3-d][1,2,3]triazole-4,9-dione (38) displayed the most potent IDO1 and TDO inhibitory activities with IC (half-maximal inhibitory concentration) values of 5 nM for IDO1 and 4 nM for TDO. It turned out that compound 38 was not a PAINS compound. Compound 38 could efficiently inhibit the biofunction of IDO1 and TDO in intact cells. In LL2 (Lewis lung cancer) and Hepa1-6 (hepatic carcinoma) allograft mouse models, this compound also showed considerable in vivo anti-tumor activity and no obvious toxicity was observed. Therefore, 38 could be a good lead compound for cancer immunotherapy and deserving further investigation.
|
Inhibition of human IDO1
|
Homo sapiens
|
71.8
nM
|
|
Journal : J Med Chem
Title : New Inhibitors of Indoleamine 2,3-Dioxygenase 1: Molecular Modeling Studies, Synthesis, and Biological Evaluation.
Year : 2016
Volume : 59
Issue : 21.0
First Page : 9760
Last Page : 9773
Authors : Coluccia A,Passacantilli S,Famiglini V,Sabatino M,Patsilinakos A,Ragno R,Mazzoccoli C,Sisinni L,Okuno A,Takikawa O,Silvestri R,La Regina G
Abstract : Indoleamine 2,3-dioxygenase 1 (IDO1) is an attractive target for anticancer therapy. Herein, we report a virtual screening study which led to the identification of compound 5 as a new IDO1 inhibitor. In order to improve the biological activity of the identified hit, arylthioindoles 6-30 were synthesized and tested. Among these, derivative 21 exhibited an IC value of 7 μM, being the most active compound of the series. Furthermore, compounds 5 and 21 induced a dose-dependent growth inhibition in IDO1 expressing cancer cell lines HTC116 and HT29. Three-dimensional quantitative structure-activity relationship studies were carried out in order to rationalize obtained results and suggest new chemical modifications.
|
Inhibition of human IDO1 incubated for 60 mins in presence of L-tryptophan by HPLC analysis
|
Homo sapiens
|
71.8
nM
|
|
Journal : J Med Chem
Title : New Inhibitors of Indoleamine 2,3-Dioxygenase 1: Molecular Modeling Studies, Synthesis, and Biological Evaluation.
Year : 2016
Volume : 59
Issue : 21.0
First Page : 9760
Last Page : 9773
Authors : Coluccia A,Passacantilli S,Famiglini V,Sabatino M,Patsilinakos A,Ragno R,Mazzoccoli C,Sisinni L,Okuno A,Takikawa O,Silvestri R,La Regina G
Abstract : Indoleamine 2,3-dioxygenase 1 (IDO1) is an attractive target for anticancer therapy. Herein, we report a virtual screening study which led to the identification of compound 5 as a new IDO1 inhibitor. In order to improve the biological activity of the identified hit, arylthioindoles 6-30 were synthesized and tested. Among these, derivative 21 exhibited an IC value of 7 μM, being the most active compound of the series. Furthermore, compounds 5 and 21 induced a dose-dependent growth inhibition in IDO1 expressing cancer cell lines HTC116 and HT29. Three-dimensional quantitative structure-activity relationship studies were carried out in order to rationalize obtained results and suggest new chemical modifications.
|
Inhibition of recombinant human IDO1 expressed in Escherichia coli BL21 (DE3) using tryptophan as substrate
|
Homo sapiens
|
47.0
nM
|
|
Journal : Eur J Med Chem
Title : A theranostic probe of indoleamine 2,3-dioxygenase 1 (IDO1) for small molecule cancer immunotherapy.
Year : 2021
Volume : 213
First Page : 113163
Last Page : 113163
Authors : Wu Y,Zhang Y,Chen X,Hu Y,Dong G,Guo Y,Sheng C
Abstract : Discovering novel small molecules for cancer immunotherapy represents a promising but challenging strategy in future cancer treatment. Herein, we designed the first theranostic fluorescent probes to efficiently detect and inhibit the enzymatic activity of 2,3-dioxygenase 1 (IDO1). Probe 6b is a highly active IDO1 inhibitor (IC = 12 nM, Cellular IC = 10 nM), which can sensitively and specifically detect endogenous IDO1 in living cells. Furthermore, as a theranostic probe, 6b showed excellent in vivo antitumor efficacy in the CT26 xenograft mouse model as well. Therefore, it can be applied as a valuable chemical tool for better understanding the immunotherapy mechanism of IDO1 and improving the therapeutic efficiency.
|
Inhibition of IDO1 in IFNgamma-stimulated human HeLa cells using tryptophan as substrate measured after 48 hrs
|
Homo sapiens
|
19.0
nM
|
|
Journal : Eur J Med Chem
Title : A theranostic probe of indoleamine 2,3-dioxygenase 1 (IDO1) for small molecule cancer immunotherapy.
Year : 2021
Volume : 213
First Page : 113163
Last Page : 113163
Authors : Wu Y,Zhang Y,Chen X,Hu Y,Dong G,Guo Y,Sheng C
Abstract : Discovering novel small molecules for cancer immunotherapy represents a promising but challenging strategy in future cancer treatment. Herein, we designed the first theranostic fluorescent probes to efficiently detect and inhibit the enzymatic activity of 2,3-dioxygenase 1 (IDO1). Probe 6b is a highly active IDO1 inhibitor (IC = 12 nM, Cellular IC = 10 nM), which can sensitively and specifically detect endogenous IDO1 in living cells. Furthermore, as a theranostic probe, 6b showed excellent in vivo antitumor efficacy in the CT26 xenograft mouse model as well. Therefore, it can be applied as a valuable chemical tool for better understanding the immunotherapy mechanism of IDO1 and improving the therapeutic efficiency.
|
Inhibition of IDO1 in human HeLa cells assessed as production of N-formylkynurenine using tryptophan as substrate in presence of inactivated fetal bovine serum
|
Homo sapiens
|
12.5
nM
|
|
|
Inhibition of recombinant human IDO1 expressed in Escherichia coli EC538 assessed as reduction in N-formylkynurenine formation using L-tryptophan as substrate incubated for 30 mins by methylene blue reagent based assay
|
Homo sapiens
|
30.0
nM
|
|
|
Inhibition of recombinant human IDO1 expressed in Escherichia coli EC538 assessed as reduction in N-formylkynurenine formation using L-tryptophan as substrate incubated for 30 mins by methylene blue reagent based concurrent assay
|
Homo sapiens
|
40.0
nM
|
|
|
Inhibition of human N-terminal His-tagged IDO1 expressed in Escherichia coli assessed as formation of N'-formyl-kynurenine using D-tryptophan as a substrate by methylene blue based assay
|
Homo sapiens
|
46.0
nM
|
|
|
Inhibition of IDO1 in mouse Panc02 cells assessed as reduction in NFK level incubated for 48 hrs by RFMS analysis
|
Mus musculus
|
74.0
nM
|
|
|
Inhibition of recombinant human His-tagged IDO1 (Ala2 to Gly403 residues) expressed in Escherichia coli using tryptophan as substrate preincubated for 10 mins followed by substrate addition and measured after 1 hr by RFMS assay
|
Homo sapiens
|
3.5
nM
|
|
|
Inhibition of IDO1 in human HeLa cells using tryptophan as substrate incubated for 24 hrs by RFMS assay
|
Homo sapiens
|
11.0
nM
|
|
|
Inhibition of IDO1 in IFNgamma-stimulated mouse Panc02 cells incubated for 48 hrs by RFMS method
|
Mus musculus
|
74.0
nM
|
|
|
In vivo inhibition of IDO1 in tumor of NSG mouse xenografted with human SKOV3 cells assessed as KYN level at 125 mg/kg, po BID administered for 5 days and measured 24 hrs post dose
|
Mus musculus
|
32.0
%
|
|
|
In vivo inhibition of IDO1 in tumor of NSG mouse xenografted with human SKOV3 cells at 200 mg/kg, po BID measured after 12 hrs by LC-MS analysis
|
Mus musculus
|
82.9
%
|
|
|
In vivo inhibition of IDO1 in plasma of NSG mouse xenografted with human SKOV3 cells at 200 mg/kg, po BID measured after 12 hrs by LC-MS analysis
|
Mus musculus
|
57.5
%
|
|
|
Inhibition of recombinant human IDO1
|
Homo sapiens
|
93.0
nM
|
|
|
Inhibition of IDO1 (unknown origin) assessed as reduction in kynurenine formation using L-tryptophan as substrate by methylene blue reagent based assay
|
Homo sapiens
|
91.0
nM
|
|
|
Inhibition of IDO1 in IFNgamma-stimulated human HeLa cells assessed as reduction in kynurenine formation measured after 48 hrs by spectrophotometry
|
Homo sapiens
|
35.76
nM
|
|
|
Inhibition of human IDO1
|
Homo sapiens
|
10.0
nM
|
|
