Read by QxMD icon Read


Shulun Chen, Zilan Song, Ao Zhang
Oncology immunotherapy has gained significant advances in recent years and benefits cancer patients with superior efficacy and superior clinical responses. Currently over ten immune checkpoint antibodies targeting CTLA-4 and PD-1/PD-L1 have received regulatory approval worldwide and over thousands are under active clinical trials. However, compared to the rapid advance of monoclonal antibody (mAb), studies on immunotherapeutic small molecules have far lagged behind. Small molecule immunotherapy not only can target immunosuppressive mechanisms similar to mAbs, but also can stimulate intracellular pathways downstream of checkpoint proteins in innate or adaptive immune cells that mAbs are unable to access...
March 8, 2019: Current Topics in Medicinal Chemistry
Thuy Phan, Vu H Nguyen, Marcela S D'Alincourt, Edwin R Manuel, Teodora Kaltcheva, Weimin Tsai, Bruce R Blazar, Don J Diamond, Laleh G Melstrom
Patients with colon cancer remain largely refractory to current immunotherapeutic strategies. This is, in part, due to the overexpression of the immune checkpoint protein indoleamine 2,3-dioxygenase 1 (IDO). IDO is an important enzyme contributing to tumor-mediated immunosuppression and also correlates with poor prognosis in colon cancer patients. The aim of this study was to assess the therapeutic efficacy of attenuated Salmonella typhimurium delivering an shRNA plasmid targeting IDO (shIDO-ST) in two mouse models of colorectal cancer...
March 1, 2019: Cancer Gene Therapy
C Robert
This year again, several breaking news were published in our field of oncodermatology, especially in the domain of immunotherapy. Many works have reported results on predictive biomarker identification. Concerning melanoma treatment, we were disappointed by the negative results of the phase III trial evaluating the IDO1 inhibitor epacadostat + pembrolizumab versus pembrolizumab. However, many promising preliminary results involving the combinations of anti-PD1 and innate immunity activators have been published...
December 2018: Annales de Dermatologie et de Vénéréologie
Troy A McEachron, Timothy J Triche, Laurie Sorenson, David M Parham, John D Carpten
Osteosarcomas are aggressive bone tumors for which therapeutic advances have not improved over several decades. Unlike most pediatric tumors, the osteosarcoma genome is remarkably unstable, characterized by numerous copy number alterations and chromosomal structural aberrations. In this study, we asked if the targetable immune checkpoints CD274 (PD-L1), PDCD1LG2 (PD-L2), CD276 (B7-H3) and IDO1 are impacted by copy number alterations in osteosarcoma. Of the 215 osteosarcoma samples investigated, PD-L1/PD-L2, B7-H3 and IDO1 were independently gained at frequencies of approximately 8-9%, with a cumulative frequency of approximately 24%...
2018: Oncoimmunology
Wenyan Wang, Xuhui Zhuang, Heyuan Sun, Lina Dong, Zongliang Liu, Guangying Du, Liang Ye, Jingwei Tian
1.S-EPA is a sulfur-substitution analogue of epacadostat (EPA), an effective small molecule indoleamine 2,3-dioxgenase1 (IDO) inhibitor. By in vitro and in vivo experiments, pharmacokinetic differences of two closely related analogs, S-EPA and EPA was investigated in this study. 2.Liver microsomes clearance experiments showed S-EPA had comparable metabolic stability with EPA in rat and human liver microsomes. The whole blood distribution experiments showed the distribution ratio of S-EPA in blood cells to plasma in mice, rats, dogs and monkey was 1...
December 3, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
Yuki Watanabe, Shohei Koyama, Atsushi Yamashita, Yunosuke Matsuura, Kensaku Nishihira, Kazuo Kitamura, Yujiro Asada
Background: Recent clinical studies have found that changes in the kynurenine (Kyn) pathway of tryptophan (Trp) metabolism are associated with cardiovascular events. However, the roles of the Kyn pathway on vascular wall thrombogenicity remain unknown. Indoleamine 2,3-dioxygenase 1 (IDO1) is a rate-limiting enzyme of the Kyn pathway. Objective: The present study aimed to localize IDO1 in human coronary atherosclerotic plaques from patients with angina pectoris and define its role in plaque thrombogenicity...
October 2018: Research and Practice in Thrombosis and Haemostasis
Takefumi Komiya, Chao H Huang
Recent application of immunotherapy in clinical oncology revolutionized our management of advanced human cancers. Check point inhibitors targeting CTLA4 and PD-1/PD-L1 axis are immunotherapeutic agents currently available to treat a variety of cancers. However, a novel therapeutic approach is needed to further improve patient outcome with these agents. Indoleamine 2,3-dioxygenase 1 (IDO1) is a rate-limiting enzyme in the metabolism of essential amino acid tryptophan in the peripheral tissue. IDO1 is overexpressed in human cancer cells and suppresses effector T cell function and promotes regulatory T cells (Tregs)...
2018: Frontiers in Oncology
(no author information available yet)
Epacadostat plus pembrolizumab achieved responses in 40% of patients with advanced solid tumors.
November 2018: Cancer Discovery
Tara C Mitchell, Omid Hamid, David C Smith, Todd M Bauer, Jeffrey S Wasser, Anthony J Olszanski, Jason J Luke, Ani S Balmanoukian, Emmett V Schmidt, Yufan Zhao, Xiaohua Gong, Janet Maleski, Lance Leopold, Thomas F Gajewski
PURPOSE: Tumors may evade immunosurveillance through upregulation of the indoleamine 2,3-dioxygenase 1 (IDO1) enzyme. Epacadostat is a potent and highly selective IDO1 enzyme inhibitor. The open-label phase I/II ECHO-202/KEYNOTE-037 trial evaluated epacadostat plus pembrolizumab, a programmed death protein 1 inhibitor, in patients with advanced solid tumors. Phase I results on maximum tolerated dose, safety, tolerability, preliminary antitumor activity, and pharmacokinetics are reported...
September 28, 2018: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
Thomas Richards, Elena Brin
Indoleamine 2,3-dioxygenase 1 (IDO1) is a new immune-oncology target and its inhibitors have shown promise in the clinic especially in combination with other immune-stimulating agents. Here we describe two robust cell-based assays for screening IDO1 inhibitors. Both assays can be easily adopted by most laboratories and utilized for screening of IDO1 inhibitors. Endogenous IDO1 expression is induced in a cancer cell line with interferon gamma and its activity is assessed by measuring kynurenine secreted into the media...
July 20, 2018: Oncotarget
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
(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
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
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
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
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
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
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
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
(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
Fetch more papers »
Fetching more papers... Fetching...
Read by QxMD. Sign in or create an account to discover new knowledge that matter to you.
Remove bar
Read by QxMD icon Read

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"