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Epacadostat

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https://www.readbyqxmd.com/read/29985683/pembrolizumab-and-epacadostat-induced-fatal-myocarditis-and-myositis-presenting-as-a-case-of-ptosis-and-ophthalmoplegia
#1
Justin B Hellman, Ilana Traynis, Lily Koo Lin
We report the first case of fatal myocarditis presenting as bilateral ptosis in a patient on combination therapy with pembrolizumab and epacadostat. An 83 year-old man with stage III high-grade urothelial carcinoma presented with acute onset droopy eyelids one month after starting pembrolizumab and epacadostat. Exam showed myogenic ptosis and ophthalmoplegia. He was later found to have acute myocarditis with complete heart block and subsequently passed away. Pembrolizumab in combination with epacadostat can induce a potentially fatal myocarditis...
July 9, 2018: Orbit
https://www.readbyqxmd.com/read/29848606/companies-scaling-back-ido1-inhibitor-trials
#2
(no author information available yet)
Based on negative results of the ECHO-301 trial in melanoma, as well as in the pancreatic cancer cohort of ECHO-203, Incyte halted several trials of its IDO inhibitor epacadostat. Other companies, including NewLink Genetics and Bristol-Myers Squibb, also decided to scale back and/or halt trials of their IDO inhibitors. However, researchers offered reasons for the disappointing trial results and said that trials of IDO inhibitors should not be abandoned.
July 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29722898/lw106-a-novel-indoleamine-2-3-dioxygenase-1-inhibitor-suppresses-tumour-progression-by-limiting-stroma-immune-crosstalk-and-cancer-stem-cell-enrichment-in-tumour-micro-environment
#3
Rong Fu, Yi-Wei Zhang, Hong-Mei Li, Wen-Cong Lv, Li Zhao, Qing-Long Guo, Tao Lu, Stephen J Weiss, Zhi-Yu Li, Zhao-Qiu Wu
BACKGROUND AND PURPOSE: Indoleamine 2,3-dioxygenase 1 (IDO1) is emerging as an important new therapeutic target for treatment of malignant tumours characterized by dysregulated tryptophan metabolism. However, the antitumour efficacy of existing small-molecule inhibitors of IDO1 is still unsatisfactory and the underlying mechanism remains largely undefined. Hence, we discovered a novel potent small-molecule inhibitor of IDO1, LW106, and studied its antitumour effects and the underlying mechanisms in two tumour models...
July 2018: British Journal of Pharmacology
https://www.readbyqxmd.com/read/29494816/4-bromophenylhydrazinyl-benzenesulfonylphenylureas-as-indoleamine-2-3-dioxygenase-inhibitors-with-in-vivo-target-inhibition-and-anti-tumor-efficacy
#4
Shu-Yu Lin, Teng-Kuang Yeh, Jen-Shin Song, Ming-Shiu Hung, Ming-Fu Cheng, Fang-Yu Liao, An-Shiou Li, Shu-Ying Cheng, Li-Mei Lin, Chun-Hsien Chiu, Mine-Hsine Wu, Yi-Jyun Lin, Wenchi Hsiao, Manwu Sun, Yi-Hsin Wang, Chin-Hsiang Huang, Ya-Chu Tang, Hsin-Huei Chang, Zih-Ting Huang, Yu-Sheng Chao, Chuan Shih, Shiow-Lin Pan, Su-Ying Wu, Ching-Chuan Kuo, Shau-Hua Ueng
Indoleamine 2,3-dioxygenase is a heme-containing enzyme implicated in the down regulation of the anti-tumor immune response, and considered a promising anti-cancer drug target. Several pharmaceutical companies, including Pfizer, Merck, and Bristol-Myers Squibb, are known to be in pursuit of IDO inhibitors, and Incyte recently reported good results in the phase II clinical trial of the IDO inhibitor Epacadostat. In previous work, we developed a series of IDO inhibitors based on a sulfonylhydrazide core structure, and explored how they could serve as potent IDO inhibitors with good drug profiles...
April 2018: Bioorganic Chemistry
https://www.readbyqxmd.com/read/29473428/a-patent-review-of-ido1-inhibitors-for-cancer
#5
REVIEW
Jae Eun Cheong, Anil Ekkati, Lijun Sun
Indoleamine 2,3-dioxygenase 1 (IDO1) is overexpressed by cancer cells and the antigen presenting dendritic cells in the tumor microenvironment (TME). Activation of IDO1 depletes tryptophan and produces kynurenine, which induces T cell anergy and suppresses tumor control by the immune system. When combined with an immune checkpoint inhibitor, IDO1 inhibitors have shown promising anticancer activity in preclinical tumor models as well as in early stage clinical trials. Areas covered: IDO1 inhibitors disclosed in the patent literature from 2013-2017 are categorized, when applicable, according to their structural similarity to the clinical development candidates indoximod and PF-06840003, navoximod, epacadostat, KHK2455 and aryl-1,2-diamines, and BMS-986205 among others, respectively...
April 2018: Expert Opinion on Therapeutic Patents
https://www.readbyqxmd.com/read/29413890/indoleamine-2-3-dioxygenase-and-its-therapeutic-inhibition-in-cancer
#6
George C Prendergast, William J Malachowski, Arpita Mondal, Peggy Scherle, Alexander J Muller
The tryptophan catabolic enzyme indoleamine 2,3-dioxygenase-1 (IDO1) has attracted enormous attention in driving cancer immunosuppression, neovascularization, and metastasis. IDO1 suppresses local CD8+ T effector cells and natural killer cells and induces CD4+ T regulatory cells (iTreg) and myeloid-derived suppressor cells (MDSC). The structurally distinct enzyme tryptophan dioxygenase (TDO) also has been implicated recently in immune escape and metastatic progression. Lastly, emerging evidence suggests that the IDO1-related enzyme IDO2 may support IDO1-mediated iTreg and contribute to B-cell inflammed states in certain cancers...
2018: International Review of Cell and Molecular Biology
https://www.readbyqxmd.com/read/29247038/discovery-of-ido1-inhibitors-from-bench-to-bedside
#7
REVIEW
George C Prendergast, William P Malachowski, James B DuHadaway, Alexander J Muller
Small-molecule inhibitors of indoleamine 2,3-dioxygenase-1 (IDO1) are emerging at the vanguard of experimental agents in oncology. Here, pioneers of this new drug class provide a bench-to-bedside review on preclinical validation of IDO1 as a cancer therapeutic target and on the discovery and development of a set of mechanistically distinct compounds, indoximod, epacadostat, and navoximod, that were first to be evaluated as IDO inhibitors in clinical trials. As immunometabolic adjuvants to widen therapeutic windows, IDO inhibitors may leverage not only immuno-oncology modalities but also chemotherapy and radiotherapy as standards of care in the oncology clinic...
December 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/29167421/structural-insights-into-substrate-and-inhibitor-binding-sites-in-human-indoleamine-2-3-dioxygenase-1
#8
Ariel Lewis-Ballester, Khoa N Pham, Dipanwita Batabyal, Shay Karkashon, Jeffrey B Bonanno, Thomas L Poulos, Syun-Ru Yeh
Human indoleamine 2,3-dioxygenase 1 (hIDO1) is an attractive cancer immunotherapeutic target owing to its role in promoting tumoral immune escape. However, drug development has been hindered by limited structural information. Here, we report the crystal structures of hIDO1 in complex with its substrate, Trp, an inhibitor, epacadostat, and/or an effector, indole ethanol (IDE). The data reveal structural features of the active site (Sa) critical for substrate activation; in addition, they disclose a new inhibitor-binding mode and a distinct small molecule binding site (Si)...
November 22, 2017: Nature Communications
https://www.readbyqxmd.com/read/29120388/synthesis-and-molecular-modeling-studies-of-n-hydroxyindazolecarboximidamides-as-novel-indoleamine-2-3-dioxygenase-1-ido1-inhibitors
#9
Dong-Ho Lee, Joo-Youn Lee, Jieun Jeong, Miok Kim, Kyung Won Lee, Eunseo Jang, Sunjoo Ahn, Chang Hoon Lee, Jong Yeon Hwang
Indoleamine 2,3-dioxygenase 1 (IDO1) is an immunosuppressive enzyme that is highly overexpressed in various cancer cells and antigen-presenting cells. It has emerged as an attractive therapeutic target for cancer immunotherapy, which has prompted high interest in the development of small-molecule inhibitors. To discover novel IDO1 inhibitors, we designed and synthesized a series of N' -hydroxyindazolecarboximidamides. Among the compounds synthesized, compound 8a inhibited both tryptophan depletion and kynurenine production through the IDO1 enzyme...
November 9, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28760910/epacadostat-shows-value-in-two-scchn-trials
#10
(no author information available yet)
In the ECHO-202/KEYNOTE-037 and ECHO-204 trials reported at the 2017 Annual Meeting of the American Society of Clinical Oncology, patients with squamous cell carcinoma of the head and neck responded well to the combinations of epacadostat plus pembrolizumab and epacadostat plus nivolumab. An IDO1 inhibitor, epacadostat also demonstrated promising activity in combination with the PD-1 checkpoint inhibitors in other solid tumors, including melanoma, urothelial carcinoma, renal cell carcinoma, and non-small cell lung cancer...
September 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28731684/the-binding-mode-of-n-hydroxyamidines-to-indoleamine-2-3-dioxygenase-1-ido1
#11
Ute F Röhrig, Vincent Zoete, Olivier Michielin
Indoleamine 2,3-dioxygenase 1 (IDO1) is an important target in cancer immunotherapy. The most advanced clinical compound, epacadostat (INCB024360), binds to the heme cofactor of IDO1 through an N-hydroxyamidine function. Conflicting binding modes have recently been proposed, reporting iron binding either through the hydroxyamidine oxygen or through the hydroxyamidine nitrogen atom. Here, we use quantum chemical calculations, docking, and quantum mechanics/molecular mechanics calculations based on available X-ray data to resolve this issue and to propose a physically meaningful binding mode...
August 22, 2017: Biochemistry
https://www.readbyqxmd.com/read/28698009/a-randomised-open-label-phase-2-study-of-the-ido1-inhibitor-epacadostat-incb024360-versus-tamoxifen-as-therapy-for-biochemically-recurrent-ca-125-relapse-only-epithelial-ovarian-cancer-primary-peritoneal-carcinoma-or-fallopian-tube-cancer
#12
RANDOMIZED CONTROLLED TRIAL
Rebecca Kristeleit, Irina Davidenko, Vadim Shirinkin, Fatima El-Khouly, Igor Bondarenko, Michael J Goodheart, Vera Gorbunova, Carol A Penning, Jack G Shi, Xiangdong Liu, Robert C Newton, Yufan Zhao, Janet Maleski, Lance Leopold, Russell J Schilder
OBJECTIVE: Indoleamine 2,3-dioxygenase-1 (IDO1) is a key regulator of immune tolerance in ovarian cancer. This study investigated efficacy and safety of the IDO1 enzyme inhibitor epacadostat versus tamoxifen in patients with biochemical-only recurrence (CA-125 elevation) following complete remission after first-line chemotherapy for advanced epithelial ovarian, primary peritoneal, or fallopian tube cancer. METHODS: In this open-label, phase 2 study (NCT01685255), patients were randomised 1:1 to epacadostat 600mg or tamoxifen 20mg twice daily for successive 28-day cycles and stratified by time since completion of first-line chemotherapy to first CA-125 elevation (3 to <12 or ≥12months)...
September 2017: Gynecologic Oncology
https://www.readbyqxmd.com/read/28523098/incb24360-epacadostat-a-highly-potent-and-selective-indoleamine-2-3-dioxygenase-1-ido1-inhibitor-for-immuno-oncology
#13
Eddy W Yue, Richard Sparks, Padmaja Polam, Dilip Modi, Brent Douty, Brian Wayland, Brian Glass, Amy Takvorian, Joseph Glenn, Wenyu Zhu, Michael Bower, Xiangdong Liu, Lynn Leffet, Qian Wang, Kevin J Bowman, Michael J Hansbury, Min Wei, Yanlong Li, Richard Wynn, Timothy C Burn, Holly K Koblish, Jordan S Fridman, Tom Emm, Peggy A Scherle, Brian Metcalf, Andrew P Combs
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...
May 11, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28283500/in-vitro-interactions-of-epacadostat-and-its-major-metabolites-with-human-efflux-and-uptake-transporters-implications-for-pharmacokinetics-and-drug-interactions
#14
Qiang Zhang, Yan Zhang, Jason Boer, Jack G Shi, Peidi Hu, Sharon Diamond, Swamy Yeleswaram
Epacadostat (EPAC) is a first-in-class, orally active inhibitor of the enzyme indoleamine 2,3-dioxygenase 1 and has demonstrated promising clinical activity. In humans, three major plasma metabolites have been identified: M9 (a glucuronide-conjugate), M11 (a gut microbiota metabolite), and M12 (a secondary metabolite formed from M11). It is proposed, based on the human pharmacokinetics of EPAC, that the biliary excretion of M9, the most abundant metabolite, leads to the enterohepatic circulation of EPAC. Using various in vitro systems, we evaluated in the present study the vitro interactions of EPAC and its major metabolites with major drug transporters involved in drug absorption and disposition...
June 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28053021/first-in-human-phase-i-study-of-the-oral-inhibitor-of-indoleamine-2-3-dioxygenase-1-epacadostat-incb024360-in-patients-with-advanced-solid-malignancies
#15
MULTICENTER STUDY
Gregory L Beatty, Peter J O'Dwyer, Jason Clark, Jack G Shi, Kevin J Bowman, Peggy A 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 I study investigated the maximum tolerated dose, safety, pharmacokinetics, pharmacodynamics, and antitumor activity of epacadostat (INCB024360), a potent and selective inhibitor of IDO1. Experimental Design: 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...
July 1, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27990653/population-pharmacokinetic-and-pharmacodynamic-modeling-of-epacadostat-in-patients-with-advanced-solid-malignancies
#16
MULTICENTER STUDY
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...
June 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/27457784/roles-of-ugt-p450-and-gut-microbiota-in-the-metabolism-of-epacadostat-in-humans
#17
Jason Boer, Ruth Young-Sciame, Fiona Lee, Kevin J Bowman, Xiaoqing Yang, Jack G Shi, Frank M Nedza, William Frietze, Laurine Galya, Andrew P Combs, Swamy Yeleswaram, Sharon Diamond
Epacadostat (EPA, INCB024360) is a first-in-class, orally active, investigational drug targeting the enzyme indoleamine 2,3-dioxygenase 1 (IDO1). In Phase I studies, EPA has demonstrated promising clinical activity when used in combination with checkpoint modulators. When the metabolism of EPA was investigated in humans, three major, IDO1-inactive, circulating plasma metabolites were detected and characterized: M9, a direct O-glucuronide of EPA; M11, an amidine; and M12, N-dealkylated M11. Glucuronidation of EPA to form M9 is the dominant metabolic pathway, and in vitro, this metabolite is formed by UGT1A9...
October 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/27451018/determination-of-epacadostat-a-novel-ido1-inhibitor-in-mouse-plasma-by-lc-ms-ms-and-its-application-to-a-pharmacokinetic-study-in-mice
#18
Vinay Dhiman, Kalpesh Kumar Giri, Suresh P S, Mohd Zainuddin, Sriram Rajagopal, Ramesh Mullangi
A sensitive, specific and rapid LC-ESI-MS/MS method has been developed and validated for the quantification of epacadostat in mouse plasma using tolbutamide as an internal standard (IS) as per regulatory guidelines. Sample preparation was accomplished through a protein precipitation. Chromatographic separation was performed on an Atlantis dC18 column using a binary gradient using mobile phase A (acetonitrile) and B (0.2% formic acid in water) at a flow rate of 0.90 mL/min. Elution of epacadostat and IS occurred at ~2...
February 2017: Biomedical Chromatography: BMC
https://www.readbyqxmd.com/read/27192116/the-ido1-selective-inhibitor-epacadostat-enhances-dendritic-cell-immunogenicity-and-lytic-ability-of-tumor-antigen-specific-t-cells
#19
Caroline Jochems, Massimo Fantini, Romaine I Fernando, Anna R Kwilas, Renee N Donahue, Lauren M Lepone, Italia Grenga, Young-Seung Kim, Martin W Brechbiel, James L Gulley, Ravi A Madan, Christopher R Heery, James W Hodge, Robert Newton, Jeffrey Schlom, Kwong Y Tsang
Epacadostat is a novel inhibitor of indoleamine-2,3-dioxygenase-1 (IDO1) that suppresses systemic tryptophan catabolism and is currently being evaluated in ongoing clinical trials. We investigated the effects of epacadostat on (a) human dendritic cells (DCs) with respect to maturation and ability to activate human tumor antigen-specific cytotoxic T-cell (CTL) lines, and subsequent T-cell lysis of tumor cells, (b) human regulatory T cells (Tregs), and (c) human peripheral blood mononuclear cells (PBMCs) in vitro...
June 21, 2016: Oncotarget
https://www.readbyqxmd.com/read/26990117/potential-underprediction-of-warfarin-drug-interaction-from-conventional-interaction-studies-and-risk-mitigation-a-case-study-with-epacadostat-an-ido1-inhibitor
#20
Jack G Shi, Xuejun Chen, Naresh G Punwani, William V Williams, Swamy Yeleswaram
Drug-drug interaction (DDI) studies involving warfarin are typically conducted with subtherapeutic doses of warfarin to ensure the safety of volunteers. However, this approach may potentially have a systemic bias of underestimating pharmacodynamic (PD) DDI effect on warfarin at therapeutic levels of anticoagulation. We demonstrate here the utility of model-based DDI prediction for a clinically relevant warfarin regimen, using the example of epacadostat (INCB024360), the first-in-class indoleamine 2,3-dioxygenase 1 inhibitor in clinical development as a novel orally active immuno-oncological therapy...
November 2016: Journal of Clinical Pharmacology
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