Development of autotaxin inhibitors: A series of zinc binding triazoles

Thomson, Christopher G.; Grand, Darren Le; Dowling, Mark R.; Brocklehurst, Cara E.; Chinn, Colin; Elphick, Lucy M.; Faller, Michael; Freeman, Mark; Furminger, Vikki; Gasser, Cornelia; Hamadi, Ahmed M.; Hardaker, Elizabeth; Head, Victoria; Hill, Johan C.; Janus, Diana; Pearce, David; Poulaud, Anne-Sophie; Stanley, Emily; Sviridenko, Lilya

doi:10.1016/j.bmcl.2018.05.030

Cited by 9 publications

(5 citation statements)

References 20 publications

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“…Several inhibitors of autotaxin that were used to determine the binding mode of the known inhibitor PF-8380 as an example, were developed by Thomson et al 160 The modification results showed that replacing the benzoxazolone fragment with a triazole zinc-binding motif decreased the crystallinity and increased solubility. Among these agents, compound 135 (Fig.…”

Section: Miscellaneous Activitiesmentioning

confidence: 99%

1,2,3-Triazole-containing hybrids as leads in medicinal chemistry: A recent overview

Bozorov

Zhao

Aisa

2019

Bioorganic & Medicinal Chemistry

580

289

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A B S T R A C TThe 1,2,3-triazole ring is a major pharmacophore system among nitrogen-containing heterocycles. These fivemembered heterocyclic motifs with three nitrogen heteroatoms can be prepared easily using 'click' chemistry with copper-or ruthenium-catalysed azide-alkyne cycloaddition reactions. Recently, the 'linker' property of 1,2,3-triazoles was demonstrated, and a novel class of 1,2,3-triazole-containing hybrids and conjugates was synthesised and evaluated as lead compounds for diverse biological targets. These lead compounds have been demonstrated as anticancer, antimicrobial, anti-tubercular, antiviral, antidiabetic, antimalarial, anti-leishmanial, and neuroprotective agents. The present review summarises advances in lead compounds of 1,2,3-triazolecontaining hybrids, conjugates, and their related heterocycles in medicinal chemistry published in 2018. This review will be useful to scientists in research fields of organic synthesis, medicinal chemistry, phytochemistry, and pharmacology. Chemistry: synthesis and properties of the 1,2,3-triazolesThe general synthetic route of 1,2,3-triazoles using click chemistry is described in Scheme 1A. The most popular route to 1,2,3-triazoles is Cu(I)-catalysed Huisgen 1,3-dipolar cycloaddition, which is the https://doi.

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Section: Miscellaneous Activitiesmentioning

confidence: 99%

1,2,3-Triazole-containing hybrids as leads in medicinal chemistry: A recent overview

Bozorov

Zhao

Aisa

2019

Bioorganic & Medicinal Chemistry

580

289

View full text Add to dashboard Cite

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“… 1 , 25 Several inhibitors of the enzyme ATX have previously been described and these have been classified by their structural binding mode into four types, type I-IV. 23 , 26 IOA-289 is shown to bind to the LPC substrate channel as well as partially blocking the base of the tunnel, designating it as a mixed type II/type IV inhibitor based on this classification, and placing it in an inhibitor class of its own. Avoidance of interaction with the enzymatic site likely contributes to the improved safety profile of IOA-289 compared with other ATX inhibitors, as this avoids off-target toxicities that were seen with first-generation entities.…”

Section: Discussionmentioning

confidence: 99%

“…Avoidance of interaction with the enzymatic site likely contributes to the improved safety profile of IOA-289 compared with other ATX inhibitors, as this avoids off-target toxicities that were seen with first-generation entities. 26 , 27 …”

Section: Discussionmentioning

confidence: 99%

Characterization and translational development of IOA-289, a novel autotaxin inhibitor for the treatment of solid tumors

Deken¹,

Niewola-Staszkowska²,

Peyruchaud³

et al. 2023

Immuno-Oncology and Technology

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“…The 5-amino-4-carboxyamido-1,2,3-triazole derivatives were assembled by a 1,3-dipolar cycloaddition between 2-cyanoacetamide or N -substituted 2-cyanoacetamides with the corresponding benzyl azides, using sodium ethoxide as a base, as previously reported [ 31 , 32 ]. Another series of N -substituted 1,2,3-triazoles, lacking the amino group on the 5-position of the heterocycle, were also prepared by Huisgen-Click cycloaddition reaction between a suitable benzyl azide and an alkyne, using the standard copper acetate/sodium ascorbate system as a catalyst [ 33 ].…”

Section: Figurementioning

confidence: 99%

Discovery of Mitochondrial Complex I Inhibitors as Anticancer and Radiosensitizer Drugs Based on Compensatory Stimulation of Lactate Release

Lan

Cadassou

Corbet

et al. 2022

Cancers

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Cancer cells may stimulate glycolytic flux when O2 becomes insufficient. Increase in L-lactate release therefore appears as an escape mechanism to drugs targeting mitochondrial respiration but also represents a response that may be exploited to screen for compounds blocking either mitochondrial carriers of oxidizable substrates or the electron transport chain. Here, we developed a screening procedure based on the capacity of cancer cells to release L-lactate to gain insights on the development of mitochondrial complex I inhibitors. For this purpose, we synthesized derivatives of carboxyamidotriazole, a compound previously described as a potential OXPHOS inhibitor. Two series of derivatives were generated by cycloaddition between benzylazide and either cyanoacetamides or alkynes. A primary assay measuring L-lactate release as a compensatory mechanism upon OXPHOS inhibition led us to identify 15 hits among 28 derivatives. A secondary assay measuring O2 consumption in permeabilized cancer cells confirmed that 12 compounds among the hits exhibited reversible complex I inhibitory activity. Anticancer effects of a short list of 5 compounds identified to induce more L-lactate release than reference compound were then evaluated on cancer cells and tumor-mimicking 3D spheroids. Human and mouse cancer cell monolayers exhibiting high level of respiration in basal conditions were up to 3-fold more sensitive than less oxidative cancer cells. 3D tumor spheroids further revealed potency differences between selected compounds in terms of cytotoxicity but also radiosensitizing activity resulting from local reoxygenation. In conclusion, this study documents the feasibility to efficiently screen in 96-well plate format for mitochondrial complex I inhibitors based on the capacity of drug candidates to induce L-lactate release.

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Development of autotaxin inhibitors: A series of zinc binding triazoles

Cited by 9 publications

References 20 publications

1,2,3-Triazole-containing hybrids as leads in medicinal chemistry: A recent overview

1,2,3-Triazole-containing hybrids as leads in medicinal chemistry: A recent overview

Characterization and translational development of IOA-289, a novel autotaxin inhibitor for the treatment of solid tumors

Discovery of Mitochondrial Complex I Inhibitors as Anticancer and Radiosensitizer Drugs Based on Compensatory Stimulation of Lactate Release

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