Natural Product-Inspired Pyranonaphthoquinone Inhibitors of Indoleamine 2,3-Dioxygenase-1 (IDO-1)

Bridewell, David J. A.; Sperry, Jonathan; Smith, Jason Scott; Kosim-Satyaputra, Priambudi; Ching, Lai Ming; Jamie, Joanne F.; Brimble, Margaret A.

doi:10.1071/ch12393

Cited by 20 publications

(15 citation statements)

References 57 publications

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“…Another study has suggested that pyranonaphthoquinone-based compounds possess dual IDO1 and topoisomerase II inhibitory activity, thus inhibiting cell growth of human H460 cells. 54,55 Compounds that integrate tumoricidal activity along with IDO1 inhibitory activity may produce substantially more robust single-agent antitumor responses than IDO1 inhibitors that do not exert a cytotoxic effect. Naphthoquinone-based compounds are reported to act as direct small-molecule inhibitors of signal transducer and activator of transcription 3 (STAT3).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Bifunctional Naphthoquinone Aromatic Amide-Oxime Derivatives Exert Combined Immunotherapeutic and Antitumor Effects through Simultaneous Targeting of Indoleamine-2,3-dioxygenase and Signal Transducer and Activator of Transcription 3

et al. 2020

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Indoleamine-2,3-dioxygenase 1 (IDO1) and signal transducer and activator of transcription 3 (STAT3) are important targets in the tumor microenvironment for cancer therapy. In the present study, a set of naphthoquinone aromatic amide-oxime derivatives were designed, which stimulated the immune response via IDO1 inhibition and simultaneously displayed powerful antitumor activity against three selected cancer cell lines through suppressing STAT3 signaling. The representative compound 8u bound effectively to IDO1, with greater inhibitory activity relative to the commercial IDO1 inhibitor 4-amino-N-(3-chloro-4-fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide (IDO5L) in addition to the efficient suppression of nuclear translocation of STAT3. Consistently, in vivo assays demonstrated a higher antiproliferative activity of compound 8u in both wild-type B16-F10 isograft tumors and an athymic HepG2 xenograft model relative to 1-methyl-l-tryptophan (1-MT) and doxorubicin (DOX). This bifunctional compound with dual immunotherapeutic and anticancer efficacy may represent a new generation of highly efficacious drug candidates for cancer therapy.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Bifunctional Naphthoquinone Aromatic Amide-Oxime Derivatives Exert Combined Immunotherapeutic and Antitumor Effects through Simultaneous Targeting of Indoleamine-2,3-dioxygenase and Signal Transducer and Activator of Transcription 3

et al. 2020

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“…In the present study, galanal was found to possess more IDO1 inhibitory potency than either the most-commonly used 1-MT or other previously-published inhibitors ( Table. 1 ) [14] [28] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] . Since the IC 50 value of inhibitor depends on the IDO1 enzyme activity in each experiment, we could not unconditionally compare the previous results.…”

Section: Discussionmentioning

confidence: 99%

“…Owing to the outstanding immune-modulate properties of IDO1, IDO1 inhibitors have been searched for in many fields, to control various inflammatory diseases. Thus, it is hoped that the inhibitor of IDO1 becomes the new therapeutic target for drugs corresponding to various inflammatory diseases [13] [14] .…”

Section: Introductionmentioning

confidence: 99%

Effects of Various Phytochemicals on Indoleamine 2,3-Dioxygenase 1 Activity: Galanal Is a Novel, Competitive Inhibitor of the Enzyme

Yamamoto

Imai

et al. 2014

PLoS ONE

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Indoleamine 2,3-dioxygenase (IDO) 1, that catalyzes the first and rate-limiting step in the degradation of L-tryptophan, has an important immunomodulatory function. The activity of IDO1 increases in various inflammatory diseases, including tumors, autoimmune diseases, and different kinds of inflammation. We evaluated the suppressive effect of plant extracts or phytochemicals on IDO1 induction and activity; sixteen kinds of plants extracts and fourteen kinds of phytochemicals were examined. As a result, the methanol extracts of Myoga flower buds, which are traditional Japanese foods, and labdane-type diterpene galanal derived from Myoga flowers significantly suppressed IDO1 activity. The Lineweaver-Burk plot analysis indicated that galanal is a competitive inhibitor. Galanal attenuated L-kynurenine formation with an IC50 value of 7.7 µM in the assay system using recombinant human IDO1, and an IC50 value of 45 nM in the cell-based assay. Further, mechanistic analysis revealed that galanal interfered with the transcriptional function of the nuclear factor-κB and the interferon-γ signaling pathway. These effects of galanal are important for immune response. Because the inhibitory effect of galanal on IDO1 activity was stronger than that of 1-methyl tryptophan, a tryptophan analog, galanal may have great potential as the novel drug for various immune-related diseases.

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“…Together with inhibitors' bound structures, the crystal structure of substrate bound state, recently resolved, brings an opportunity to develop new rationales on the development of IDO1 inhibitors. Therefore, even though great efforts have been made to develop IDO1 inhibitors using structure‐based design, high throughput screening (HTS) and natural product screening are still ongoing and successfully yielded different active scaffolds …”

Section: Indoleamine 23‐dioxygenase1mentioning

confidence: 99%

Computer‐aided drug design in new druggable targets for the next generation of immune‐oncology therapies

Acúrcio

Scomparin

Satchi‐Fainaro

et al. 2018

WIREs Comput Mol Sci

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all approved immune checkpoint modulators in the clinic are monoclonal antibodies. These have revolutionized cancer therapy because of their remarkable clinical activity. However, their failure to show response in most patients, their required administration by an intravenous injection and the induction of severe immune-related adverse effects, 1-3 constitute some of their important drawbacks.In this context, considerable research effort is being deployed to find the next generation of effective cancer immunotherapeutics. Pioneering efforts include the design of novel immune modulatory small molecules (synthetic and natural products) to specifically target emerging pathways responsible for immune evasion. Small molecules are more affordable and may become invaluable alternatives to monoclonal antibodies. However, small-molecule drug discovery is a complex and challenging multidimensional process, focusing on multiple aspects, as the activity, efficacy, pharmacokinetics, pharmacodynamics, and safety of potential novel candidates. The average length of time from hit discovery to the approval of a new drug is at least 14 years, encompassing the investment of billions of dollars. To circumvent and accelerate this lengthy and costly drug discovery and development process, over the past two decades, drug designers have been exploring computational-aided drug design (CADD) tools to design and identify new drug-like chemical entities that can overcome clinical attrition and lack of efficiency.Revolutionary and accelerated performance hardware architectures, including graphical processor units, innovative algorithms and software advances are now available for high-level computations in a time-affordable way pushing the frontiers of computationally driven drug discovery in the rational search for novel bioactive compounds in modern medicinal chemistry.CADD methodologies can be divided in structure-and ligand-based drug design (SBDD and LBDD). Protein three-dimensional (3D) structures are the basis for structure-based drug design. Once the 3D structure of a protein target is available, the SBDD is usually elected to develop therapeutic agents and to understand the mode of action, as well as, the metabolic process. SBDD embraces several methodologies, namely structure-based virtual screening (SBVS), de novo design or pharmacophore generation. A rational SBDD approach is based on the deep understanding of the key interactions between small molecules (or proteins) and their targets, applying techniques, such as molecular docking and molecular dynamics (Scheme 1).Broadly used for SBVS, molecular docking methods explore the ligand conformations adopted within the binding sites of macromolecular targets (search algorithm) and estimate the ligand-receptor affinities (scoring functions). Molecular docking is nowadays one of the elected methods to use in SBVS with a huge rate of success. However, molecular docking works on rigid structures forgetting structural flexibility and structural rearrangements. Although this is a generally ...

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Natural Product-Inspired Pyranonaphthoquinone Inhibitors of Indoleamine 2,3-Dioxygenase-1 (IDO-1)

Cited by 20 publications

References 57 publications

Bifunctional Naphthoquinone Aromatic Amide-Oxime Derivatives Exert Combined Immunotherapeutic and Antitumor Effects through Simultaneous Targeting of Indoleamine-2,3-dioxygenase and Signal Transducer and Activator of Transcription 3

Bifunctional Naphthoquinone Aromatic Amide-Oxime Derivatives Exert Combined Immunotherapeutic and Antitumor Effects through Simultaneous Targeting of Indoleamine-2,3-dioxygenase and Signal Transducer and Activator of Transcription 3

Effects of Various Phytochemicals on Indoleamine 2,3-Dioxygenase 1 Activity: Galanal Is a Novel, Competitive Inhibitor of the Enzyme

Computer‐aided drug design in new druggable targets for the next generation of immune‐oncology therapies

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