The first indoleamine-2,3-dioxygenase-1 (IDO1) inhibitors containing carborane

Austin, Christopher; Kahlert, Jan; Issa, F. G.; Reed, John H.; Smith, Jason Scott; Ioppolo, Joseph A.; Ong, Jennifer; Jamie, Joanne F.; Hibbs, David E.; Rendina, Louis M.

doi:10.1039/c4dt00444b

Cited by 21 publications

(10 citation statements)

References 29 publications

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“…Exciting developments in tryptophan metabolism research have been achieved within the past 5 years including: the discovery and characterisation of new dioxygenase enzymes; elucidation of new functional roles for established proteins; the development of second-and third-generation [72] IDO1 inhibitors; and ongoing investigations of IDO1 inhibition via clinical trials. Given the multifaceted role that tryptophan-kynurenine metabolism has in the immune response, it appears increasingly likely that future immunomodulatory regimens (particularly in relation to cancer chemotherapy) will target this important pathway.…”

Section: Discussionmentioning

confidence: 99%

Targeting key dioxygenases in tryptophan–kynurenine metabolism for immunomodulation and cancer chemotherapy

Austin

Rendina

2015

Drug Discovery Today

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Section: Discussionmentioning

confidence: 99%

Targeting key dioxygenases in tryptophan–kynurenine metabolism for immunomodulation and cancer chemotherapy

Austin

Rendina

2015

Drug Discovery Today

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“…Several, structurally diverse classes of potent small-molecule IDO1 dioxygenase activity inhibitors have been reported (reviewed in [417]), e.g. 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].…”

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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“…Their unique reactivity allows for ease of derivatization of either of the CH vertices and regioselective modification of select boron atoms within the cage, in high yield [18][19][20][21][22][23][24]. Carboranes have been incorporated into small molecules as hydrophobic pharmacophores [5,[24][25][26][27][28][29][30][31][32][33][34], novel biomaterials including liposomes [14,35], and dendrimers [36,37]. They have also been used as boron-rich bioconjugates, including antibody-linked clusters [38].…”

Section: Introductionmentioning

confidence: 99%