Discovery and characterisation of hydrazines as inhibitors of the immune suppressive enzyme, indoleamine 2,3-dioxygenase 1 (IDO1)

Fung, Simon; Wang, Haiyan; Tomek, Petr; Squire, C.J.; Flanagan, Jack U.; Palmer, Brian D.; Bridewell, David J. A.; Tijono, Sofian; Jamie, Joanne F.; Ching, Lai Ming

doi:10.1016/j.bmc.2013.10.037

Cited by 29 publications

(20 citation statements)

References 39 publications

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“…Gratifyingly, a screen of a few dozen commercial compounds yielded several micromolar or sub-micromolar potency molecules. Similar to the recent report from the Ching group 20 , phenylhydrazine was found to be a highly potent inhibitor of IDO1. This is not surprising since phenylhydrazine has been found to interact with other heme-containing proteins, such as hemoglobin, 22 cytochrome P450, 23 catalase 24 and myoglobin 25 .…”

Section: Resultssupporting

confidence: 86%

“…To simplify compound 3 , the alkylperoxy moiety is further reduced to Ar-C-X-Y, where Ar is an aryl ring and C is a linker containing a carbon moiety (such as methylene or carbonyl). In related work, two previously reported IDO1 inhibitors in the scientific literature demonstrate a similar theme in their inhibitor design: The hydroxyamidines reported in 2009 by Incyte 19 and the recent report of alkylhydrazine derivative inhibitory activity by Ching et al 20 . Neither of these reports discussed the potential mimicry of the proposed alkylperoxy intermediate or related rational design idea.…”

Section: Introductionmentioning

confidence: 73%

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O-alkylhydroxylamines as rationally-designed mechanism-based inhibitors of indoleamine 2,3-dioxygenase-1

Malachowski

Winters

DuHadaway

et al. 2016

European Journal of Medicinal Chemistry

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Indoleamine 2,3-dioxygenase-1 (IDO1) is a promising therapeutic target for the treatment of cancer, chronic viral infections, and other diseases characterized by pathological immune suppression. Recently important advances have been made in understanding IDO1’s catalytic mechanism. Although much remains to be discovered, there is strong evidence that the mechanism proceeds through a heme-iron bound alkylperoxy transition or intermediate state. Accordingly, we explored stable structural mimics of the alkylperoxy species and provide evidence that such structures do mimic the alkylperoxy transition or intermediate state. We discovered that O-benzylhydroxylamine, a commercially available compound, is a potent sub-micromolar inhibitor of IDO1. Structure-activity studies of over forty derivatives of O-benzylhydroxylamine led to further improvement in inhibitor potency, particularly with the addition of halogen atoms to the meta position of the aromatic ring. The most potent derivatives and the lead, O-benzylhydroxylamine, have high ligand efficiency values, which are considered an important criterion for successful drug development. Notably, two of the most potent compounds demonstrated nanomolar-level cell-based potency and limited toxicity. The combination of the simplicity of the structures of these compounds and their excellent cellular activity makes them quite attractive for biological exploration of IDO1 function and antitumor therapeutic applications.

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Section: Resultssupporting

confidence: 86%

Section: Introductionmentioning

confidence: 73%

O-alkylhydroxylamines as rationally-designed mechanism-based inhibitors of indoleamine 2,3-dioxygenase-1

Malachowski

Winters

DuHadaway

et al. 2016

European Journal of Medicinal Chemistry

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“…brassinins [418], hydroxyamidines [130,419,420], naphthoquinones [421,422], methyl-thiohydantoin-tryptophan [120], imidazoles (e.g. phenylimadazole and imidazolethiazoles) [129,423,424], exiguamines [425], triazoles [426], indoles [427,428], selenazoles [135] and hydrazines [129,429]. A recent high-throughput screen of major available drug libraries highlighted the potential challenges surrounding the discovery of selective and potent small-molecule inhibitors of IDO1 [424].…”

Section: Ido1 Inhibitors As Putative Immunotherapeutic Anticancer Drugsmentioning

confidence: 99%

Role of indoleamine 2,3-dioxygenase in health and disease

et al. 2015

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IDO1 (indoleamine 2,3-dioxygenase 1) is a member of a unique class of mammalian haem dioxygenases that catalyse the oxidative catabolism of the least-abundant essential amino acid, L-Trp (L-tryptophan), along the kynurenine pathway. Significant increases in knowledge have been recently gained with respect to understanding the fundamental biochemistry of IDO1 including its catalytic reaction mechanism, the scope of enzyme reactions it catalyses, the biochemical mechanisms controlling IDO1 expression and enzyme activity, and the discovery of enzyme inhibitors. Major advances in understanding the roles of IDO1 in physiology and disease have also been realised. IDO1 is recognised as a prominent immune regulatory enzyme capable of modulating immune cell activation status and phenotype via several molecular mechanisms including enzyme-dependent deprivation of L-Trp and its conversion into the aryl hydrocarbon receptor ligand kynurenine and other bioactive kynurenine pathway metabolites, or non-enzymatic cell signalling actions involving tyrosine phosphorylation of IDO1. Through these different modes of biochemical signalling, IDO1 regulates certain physiological functions (e.g. pregnancy) and modulates the pathogenesis and severity of diverse conditions including chronic inflammation, infectious disease, allergic and autoimmune disorders, transplantation, neuropathology and cancer. In the present review, we detail the current understanding of IDO1's catalytic actions and the biochemical mechanisms regulating IDO1 expression and activity. We also discuss the biological functions of IDO1 with a focus on the enzyme's immune-modulatory function, its medical implications in diverse pathological settings and its utility as a therapeutic target.

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“…However, they also showed a differential selectivity for those derivates, as 1-propyl-tryptophan (1-PT) and 1-isopropyltryptophan (1-isoPT) moderately inhibited IDO1 expression and enzymatic activity in dendritic cells, whereas 1-butyl-tryptophan (1-BT) and 1-ethyl-tryptophan (1-ET) mainly suppressed IDO2 expression. Fung et al discovered that phenylhydrazine, a hydrazine derivative, potently inhibited IDO1 at nontoxic concentrations, after screening of a fragment library (Fung et al 2013 ). Muller et al suggested the use of another novel IDO inhibitor, the ethyl pyruvate, as they demonstrated that ethyl pyruvate suppressed the expression of IDO1 in vitro in IFNγ-and LPS-stimulated U937 human lymphoma cells and inhibited tumor growth in a T-cell-dependent manner in murine B16-F10 melanoma and Bin1 −/− MR KEC (Myc + ras-transformed keratinocytes from Bin1 defi cient mice) tumor models in vivo (Muller et al 2010 ).…”

Section: The Use Of Ido Inhibitors With Chemotherapy And/or Tumor Vacmentioning

confidence: 97%

Chemotherapeutic Agents in Cancer Treatment and Tryptophan Metabolism

Kesikli

Güler

2015

Tryptophan Metabolism: Implications for Biological Processes, Health and Disease

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Cancer is the uncontrolled division and accumulation of cells in any part of the body. Surgery, radiotherapy, and systemic therapies are the main treatment strategies against cancers. However, systemic chemotherapy has various side effects, including nausea, vomiting, myelosuppression, cardiotoxicity (with anthracyclines), neurotoxicity (with mitotic spindle poisons), and nephrotoxicity (with platinum analogs). Although surgery can be curative in some cases, the main purposes of cancer treatments, especially in metastatic cancer patients, are the palliation of symptoms and increasing survival with better quality of life. Increasing the effi cacy and decreasing the toxicity of chemotherapeutic agents are currently the main challenges in cancer treatment, for which substantial effort has been given for years. Melatonin is a hormone produced in the pineal gland from the essential amino acid tryptophan. It is one of the strongest antioxidants identifi ed, with additional chemopreventive, oncostatic, and tumor inhibitory effects in a variety of in vitro and in vivo experimental cancer models. In addition to melatonin synthesis, tryptophan is involved in numerous metabolic activities in the human body, including the biosynthesis of serotonin, kynurenine, and nicotinamide, thereby regulating circadian rhythm, learning, memory, sleep, behavior, mood, appetite, aging, growth, reproduction, immune system, and cancer development. Therefore, tryptophan-related metabolic pathways and catabolites have gained considerable attention, especially in improving cancer treatment and predicting disease activity as well as patient survival. This chapter mainly focuses on the relationship between tryptophan metabolism and chemotherapy; the prognostic value of tryptophan catabolites as cancer biomarkers, tryptophan metabolism, and cancer-related fatigue; the association between melatonin and cancer therapy as well as chemotherapy side effects;

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Discovery and characterisation of hydrazines as inhibitors of the immune suppressive enzyme, indoleamine 2,3-dioxygenase 1 (IDO1)

Cited by 29 publications

References 39 publications

O-alkylhydroxylamines as rationally-designed mechanism-based inhibitors of indoleamine 2,3-dioxygenase-1

O-alkylhydroxylamines as rationally-designed mechanism-based inhibitors of indoleamine 2,3-dioxygenase-1

Role of indoleamine 2,3-dioxygenase in health and disease

Chemotherapeutic Agents in Cancer Treatment and Tryptophan Metabolism

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