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https://www.readbyqxmd.com/read/28053021/first-in-human-phase-1-study-of-the-oral-inhibitor-of-indoleamine-2-3-dioxygenase-1-epacadostat-incb024360-in-patients-with-advanced-solid-malignancies
#1
Gregory L Beatty, Peter J O'Dwyer, Jason Clark, Jack G Shi, Kevin J Bowman, Peggy Scherle, Robert C Newton, Richard Schaub, Janet Maleski, Lance Leopold, Thomas F Gajewski
PURPOSE: Indoleamine 2,3-dioxygenase-1 (IDO1) catalyzes the degradation of tryptophan to N-formyl-kynurenine. Overexpressed in many solid malignancies, IDO1 can promote tumor escape from host immunosurveillance. This first-in-human phase 1 study investigated the maximum tolerated dose, safety, pharmacokinetics, pharmacodynamics, and antitumor activity of epacadostat (INCB024360), a potent and selective inhibitor of IDO1. PATIENTS AND METHODS: Fifty-two patients with advanced solid malignancies were treated with epacadostat (50 mg once daily or 50, 100, 300, 400, 500, 600, or 700 mg twice daily [BID]) in a dose-escalation 3 + 3 design and evaluated in 28-day cycles...
January 4, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28027300/gene-expression-differences-in-prostate-cancers-between-young-and-old-men
#2
Yuanchun Ding, Huiqing Wu, Charles Warden, Linda Steele, Xueli Liu, M van Iterson, Xiwei Wu, Rebecca Nelson, Zheng Liu, Yate-Ching Yuan, Susan L Neuhausen
Prostate cancer incidence is increasing in younger men. We investigated whether men diagnosed with Gleason 7 (3+4) T2 prostate cancer at younger ages (≤ 45 years, young cohort) had different mRNA and miRNA expression profiles than men diagnosed at older ages (71-74 years, older cohort). We identified differentially expressed genes (DEGs) related to tumor-normal differences between the cohorts. Subsequent pathway analysis of DEGs revealed that the young cohort had significantly more pronounced inflammatory and immune responses to tumor development compared to the older cohort...
December 2016: PLoS Genetics
https://www.readbyqxmd.com/read/28011425/discovery-and-evaluation-of-inhibitors-to-the-immunosuppressive-enzyme-indoleamine-2-3-dioxygenase-1-ido1-probing-the-active-site-inhibitor-interactions
#3
Petr Tomek, Brian D Palmer, Jack U Flanagan, Chuanwen Sun, Emma L Raven, Lai-Ming Ching
High expression of the immunosuppressive enzyme, indoleamine 2,3-dioxygenase 1 (IDO1) for a broad range of malignancies is associated with poor patient prognosis, and the enzyme is a validated target for cancer intervention. To identify novel IDO1 inhibitors suitable for drug development, 1597 compounds in the National Cancer Institute Diversity Set III library were tested for inhibitory activity against recombinant human IDO1. We retrieved 35 hits that inhibited IDO1 activity >50% at 20 μM. Five structural filters and the PubChem Bioassay database were used to guide the selection of five inhibitors with IC50 between 3 and 12 μM for subsequent experimental evaluation...
December 13, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28004656/co-delivery-of-indoleamine-2-3-dioxygenase-prevents-loss-of-expression-of-an-antigenic-transgene-in-dystrophic-mouse-muscles
#4
D Sharma, R Al-Khalidi, S Edgar, Q An, Y Wang, C Young, D Nowis, D C Gorecki
A significant problem affecting gene therapy approaches aiming at achieving long-term transgene expression is the immune response against the protein product of the therapeutic gene, which can reduce or eliminate the therapeutic effect. The problem is further exacerbated when therapy involves targeting an immunogenic tissue and/or one with a pre-existing inflammatory phenotype, such as dystrophic muscles. In this proof-of-principle study, we co-expressed a model antigen, bacterial β-galactosidase, with an immunosuppressive factor, indoleamine 2,3-dioxygenase 1 (IDO1), in muscles of the mdx mouse model of Duchenne muscular dystrophy...
December 22, 2016: Gene Therapy
https://www.readbyqxmd.com/read/27994758/fused-heterocyclic-compounds-as-potent-indoleamine-2-3-dioxygenase-1-inhibitors
#5
Subhankar Panda, Ashalata Roy, Suman Jyoti Deka, Vishal Trivedi, Debasis Manna
Uncontrolled metabolism of l-tryptophan (l-Trp) in the immune system has been recognized as a critical cellular process in immune tolerance. Indoleamine 2,3-dioxygenase 1 (IDO1) enzyme plays an important role in the metabolism of a local l-Trp through the kynurenine pathway in the immune systems. In this regard, IDO1 has emerged as a therapeutic target for the treatment of diseases that are associated with immune suppression like chronic infections, cancer, and others. In this study, we synthesized a series of pyridopyrimidine, pyrazolopyranopyrimidine, and dipyrazolopyran derivatives...
December 8, 2016: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27994058/signal-transducer-and-activator-of-transcription-1-plays-a-pivotal-role-in-ret-ptc3-oncogene-induced-expression-of-indoleamine-2-3-dioxygenase-1
#6
Sonia Moretti, Elisa Menicali, Nicole Nucci, Pasquale Voce, Renato Colella, Rosa Marina Melillo, Federica Liotti, Silvia Morelli, Francesca Fallarino, Antonio Macchiarulo, Massimo Santoro, Nicola Avenia, Efisio Puxeddu
Indoleamine 2,3-dioxygenase 1 (IDO1) is a single chain oxidoreductase that catalyzes tryptophan degradation to kynurenine. In cancer, it exerts an immunosuppressive function as part of an acquired mechanism of immune-escape. Recently, we demonstrated that IDO1 expression is significantly higher in all thyroid cancer histotypes compared to normal thyroid and that its expression levels correlate with T regulatory (Treg) lymphocyte densities in the tumor microenvironment. BRAFV600E- and RET/PTC3-expressing PcCL3 cells were used as cellular models for the evaluation of IDO1 expression in thyroid carcinoma cells and for the study of involved signal transduction pathways...
December 19, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27990653/population-pharmacokinetic-and-pharmacodynamic-modeling-of-epacadostat-in-patients-with-advanced-solid-malignancies
#7
Jack G Shi, Kevin J Bowman, Xuejun Chen, Janet Maleski, Lance Leopold, Swamy Yeleswaram
Epacadostat (EPA, INCB024360) is a selective inhibitor of the enzyme indoleamine 2,3-dioxygenase 1 (IDO1) and is being developed as an orally active immunotherapy to treat advanced malignancies. In the first clinical study investigating the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of EPA in oncology patients, increasing doses of EPA ranging from 50 mg once daily to 700 mg twice daily were administered as a monotherapy to 52 subjects with advanced solid tumors. The EPA plasma concentration-time profiles were adequately described by a population PK model comprised of the first-order kinetics of oral absorption with 2-compartment distribution and constant clearance from the central compartment...
December 19, 2016: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/27914477/in-vitro-rescue-of-genital-strains-of-chlamydia-trachomatis-from-interferon-%C3%AE-and-tryptophan-depletion-with-indole-positive-but-not-indole-negative-prevotella-spp
#8
Noa Ziklo, Wilhelmina M Huston, Kuong Taing, Mohammad Katouli, Peter Timms
BACKGROUND: The natural course of sexually transmitted infections caused by Chlamydia trachomatis varies between individuals. In addition to parasite and host effects, the vaginal microbiota might play a key role in the outcome of C. trachomatis infections. Interferon-gamma (IFN-γ), known for its anti-chlamydial properties, activates the expression of indoleamine 2,3-dioxygenase (IDO1) in epithelial cells, an enzyme that catabolizes the amino acid L- tryptophan into N-formylkynurenine, depleting the host cell's pool of tryptophan...
December 3, 2016: BMC Microbiology
https://www.readbyqxmd.com/read/27910911/human-mesenchymal-stem-cells-program-macrophage-plasticity-by-altering-their-metabolic-status-via-a-pge2-dependent-mechanism
#9
Anoop Babu Vasandan, Sowmya Jahnavi, Chandanala Shashank, Priya Prasad, Anujith Kumar, S Jyothi Prasanna
Mesenchymal stem cells (MSCs) are speculated to act at macrophage-injury interfaces to mediate efficient repair. To explore this facet in-depth this study evaluates the influence of MSCs on human macrophages existing in distinct functional states. MSCs promoted macrophage differentiation, enhanced respiratory burst and potentiated microbicidal responses in naïve macrophages (Mφ). Functional attenuation of inflammatory M1 macrophages was associated with a concomitant shift towards alternatively activated M2 state in MSC-M1 co-cultures...
December 2, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27906184/1-methyl-tryptophan-attenuates-regulatory-t-cells-differentiation-due-to-the-inhibition-of-estrogen-ido1-mrc2-axis-in-endometriosis
#10
Chunyan Wei, Jie Mei, Lingli Tang, Yukai Liu, Dajin Li, Mingqing Li, Xiaoyong Zhu
Foxp3(+) regulatory T (Treg) cells contribute to the local dysfunctional immune environment in endometriosis, an estrogen-dependent gynecological disease, which affects the function of ectopic endometrial tissue clearance by the immune system. The reason for the high percentage of peritoneal Treg in endometriosis patients is unknown. Here, we show that the proportion of peritoneal Treg cells increases as endometriosis progresses. To determine the probable mechanism, we established a naive T cell-macrophage-endometrial stromal cell (ESC) co-culture system to mimic the peritoneal cavity microenvironment...
December 1, 2016: Cell Death & Disease
https://www.readbyqxmd.com/read/27891058/ido2-a-pathogenic-mediator-of-inflammatory-autoimmunity
#11
REVIEW
Lauren M F Merlo, Laura Mandik-Nayak
Indoleamine 2,3-dioxygenase 2 (IDO2), a homolog of the better-studied tryptophan-catabolizing enzyme IDO1, is an immunomodulatory molecule with potential effects on various diseases including cancer and autoimmunity. Here, we review what is known about the direct connections between IDO2 and immune function, particularly in relationship to autoimmune inflammatory disorders such as rheumatoid arthritis and lupus. Accumulating evidence indicates that IDO2 acts as a pro-inflammatory mediator of autoimmunity, with a functional phenotype distinct from IDO1...
2016: Clinical Medicine Insights. Pathology
https://www.readbyqxmd.com/read/27889479/ido1-is-an-integral-mediator-of-inflammatory-neovascularization
#12
Arpita Mondal, Courtney Smith, James B DuHadaway, Erika Sutanto-Ward, George C Prendergast, Arturo Bravo-Nuevo, Alexander J Muller
The immune tolerogenic effects of IDO1 (indoleamine 2,3-dioxygenase 1) have been well documented and genetic studies in mice have clearly established the significance of IDO1 in tumor promotion. Dichotomously, the primary inducer of IDO1, the inflammatory cytokine IFNγ (interferon-γ), is a key mediator of immune-based tumor suppression. One means by which IFNγ can exert an anti-cancer effect is by decreasing tumor neovascularization. We speculated that IDO1 might contribute to cancer promotion by countering this anti-neovascular effect of IFNγ, possibly through IDO1-potentiated elevation of the pro-tumorigenic inflammatory cytokine IL6 (interleukin-6)...
December 2016: EBioMedicine
https://www.readbyqxmd.com/read/27877172/regulated-inflammation-and-lipid-metabolism-in-colon-mrna-expressions-of-obese-germfree-mice-responding-to-enterobacter-cloacae-b29-combined-with-the-high-fat-diet
#13
Huiying Yan, Na Fei, Guojun Wu, Chenhong Zhang, Liping Zhao, Menghui Zhang
Increased evidences have demonstrated that gut microbiota targeted diet intervention can alleviate obesity and related metabolic disorders. The underlying mechanism of interactions among diet, microbiota, and host still remains unclear. Enterobacter cloacae B29, an endotoxin-producing strain dominated in the gut of a morbidly obese volunteer (weight 174.8 kg, BMI 58.8 kg m(-2)) was isolated and transplanted to germfree mice (inoculated 10(10) cells of B29 per day for 1 week). Using deep mRNA sequencing technology, we compared different gene expression profiles in the colon samples of the germfree mice treated with/without B29 and/or high fat diet (HFD) for 16 weeks and identified 279 differential expressed genes in total, including up-regulated genes Apoa4 (fold change, 2...
2016: Frontiers in Microbiology
https://www.readbyqxmd.com/read/27863031/discovery-of-a-novel-scaffold-as-an-indoleamine-2-3-dioxygenase%C3%A2-1-ido1-inhibitor-based-on-the-pyrrolopiperazinone-alkaloid-longamide%C3%A2-b
#14
Zenyu Shiokawa, Emi Kashiwabara, Daisuke Yoshidome, Koichi Fukase, Shinsuke Inuki, Yukari Fujimoto
Indoleamine 2,3-dioxygenase 1 (IDO1) has emerged as a key target for cancer therapy, as IDO1 plays a critical role in the capacity of tumor cells to evade the immune system. The pyrrolopiperazinone alkaloid longamide B and its derivatives were identified as novel IDO1 inhibitors based on docking studies and small library synthesis. The thioamide derivative showed higher IDO1 inhibitory activity than longamide B, and displayed an activity similar to that of a representative IDO1 inhibitor, 1-methyl-tryptophan...
December 16, 2016: ChemMedChem
https://www.readbyqxmd.com/read/27860276/regulation-of-kynurenine-biosynthesis-during-influenza-virus-infection
#15
Lana Gaelings, Sandra Söderholm, Andrii Bugai, Yu Fu, Jatin Nandania, Bert Schepens, Martina B Lorey, Janne Tynell, Liesbeth Vande Ginste, Ronan Le Goffic, Matthew S Miller, Marika Kuisma, Varpu Marjomäki, Jef De Brabander, Sampsa Matikainen, Tuula A Nyman, Dennis H Bamford, Xavier Saelens, Ilkka Julkunen, Henrik Paavilainen, Veijo Hukkanen, Vidya Velagapudi, Denis E Kainov
Influenza A viruses (IAVs) remain serious threats to public health because of the shortage of effective means of control. Developing more effective virus control modalities requires better understanding of virus-host interactions. It has previously been shown that IAV induces the production of kynurenine, which suppresses T-cell responses, enhances pain hypersensitivity and disturbs behaviour in infected animals. However, the regulation of kynurenine biosynthesis during IAV infection remains elusive. Here we showed that IAV infection induced expression of interferons (IFNs), which upregulated production of indoleamine-2,3-dioxygenase (IDO1), which catalysed the kynurenine biosynthesis...
November 18, 2016: FEBS Journal
https://www.readbyqxmd.com/read/27828964/chronic-treatment-with-the-ido1-inhibitor-1-methyl-d-tryptophan-minimizes-the-behavioural-and-biochemical-abnormalities-induced-by-unpredictable-chronic-mild-stress-in-mice-comparison-with-fluoxetine
#16
Anthony Laugeray, Jean-Marie Launay, Jacques Callebert, Oguz Mutlu, Gilles J Guillemin, Catherine Belzung, Pascal R Barone
We demonstrated that confronting mice to the Unpredictable Chronic Mild Stress (UCMS) procedure-a validated model of stress-induced depression-results in behavioural alterations and biochemical changes in the kynurenine pathway (KP), suspected to modify the glutamatergic neurotransmission through the imbalance between downstream metabolites such as 3-hydroxykynurenine, quinolinic and kynurenic acids. We showed that daily treatment with the IDO1 inhibitor 1-methyl-D-tryptophan partially rescues UCMS-induced KP alterations as does the antidepressant fluoxetine...
2016: PloS One
https://www.readbyqxmd.com/read/27819068/the-kynurenine-tryptophan-ratio-and-glioblastoma-patients-treated-with-hsppc-96-vaccine
#17
Alicia Lenzen, Lijie Zhai, Kristen L Lauing, Galina Gritsina, Erik Ladomersky, Matthew Genet, C David James, Orin Bloch, Derek A Wainwright
The discovery that immunotherapy is a clinically-relevant approach for the treatment of malignant tumors is revolutionizing patient care. In adults diagnosed with glioblastoma (GBM), an aggressive and incurable primary brain tumor, autologous HSPPC-96 vaccination provides a significant increase in overall survival. However, all GBM patients eventually succumb to their disease, providing rationale for discovering new methods that proactively identify individuals that will respond, optimally. Of the immunosuppressive mediators that contribute to the inhibition of productive tumor immunity, indoleamine 2,3 dioxygenase 1 (IDO1), a rate-limiting enzyme that catabolizes tryptophan (Trp) into kynurenine (Kyn), has been demonstrated to be expressed at elevated levels in patients with malignant glioma...
September 2016: Immunotherapy (Los Angeles, Calif.)
https://www.readbyqxmd.com/read/27799931/immunomodulatory-factors-galectin-9-and-interferon-gamma-synergize-to-induce-expression-of-rate-limiting-enzymes-of-the-kynurenine-pathway-in-the-mouse-hippocampus
#18
Alexandra K Brooks, Marcus A Lawson, Jennifer L Rytych, Kevin C Yu, Tiffany M Janda, Andrew J Steelman, Robert H McCusker
Elevated levels of circulating pro-inflammatory cytokines are associated with symptomology of several psychiatric disorders, notably major depressive disorder. Symptomology has been linked to inflammation/cytokine-dependent induction of the Kynurenine Pathway. Galectins, like pro-inflammatory cytokines, play a role in neuroinflammation and the pathogenesis of several neurological disorders but without a clearly defined mechanism of action. Their involvement in the Kynurenine Pathway has not been investigated...
2016: Frontiers in Immunology
https://www.readbyqxmd.com/read/27769672/discovery-and-preliminary-structure-activity-relationship-of-1h-indazoles-with-promising-indoleamine-2-3-dioxygenase-1-ido1-inhibition-properties
#19
Shan Qian, Tao He, Wei Wang, Yanying He, Man Zhang, Lingling Yang, Guobo Li, Zhouyu Wang
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...
October 6, 2016: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/27769618/novel-substituted-hydrazono-indolo-2-1-b-quinazoline-6-12-dione-analogues-as-cytostatic-agents-synthesis-crystal-structure-biological-evaluation-and-molecular-docking-studies
#20
Ramu Guda, Sirassu Narsimha, Ramavath Babu, Srujana Muthadi, Harikiran Lingabathula, Rambabu Palabindela, Narsimha Reddy Yellu, Girijesh Kumar, Mamatha Kasula
A series of novel substituted hydrazono indolo[2,1-b]quinazoline-6,12-dione analogues have been synthesized and screened for their in vitro cytotoxic and antimicrobial activities. Among all the target compounds, 3c exhibited the most potent inhibitory activity against three cancer cell lines MCF-7, A549, HeLa with IC50 values 07.14±1.285μM, 09.18±0.968μM and 10.57±0.581μM respectively, while maintaining low toxicity towards non-cancer originated cell line, HEK-293. The detailed studies about molecular interactions with probable target protein indoleamine 2,3-dioxygenase (IDO1) were done by using docking simulations...
November 15, 2016: Bioorganic & Medicinal Chemistry Letters
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