Mixed-ligand copper(II) complexes activate aryl hydrocarbon receptor AhR and induce CYP1A genes expression in human hepatocytes and human cell lines

Kubešová, Kateřina; Doricakova, Aneta; Trávníček, Zdeněk; Dvořák, Zdeněk

doi:10.1016/j.toxlet.2016.05.014

Cited by 6 publications

(3 citation statements)

References 31 publications

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“…HepaRG cells simulate hepatocytes in that PXR ligands can also induce target genes in a similar but not identical manner (Aninat et al , ; Andersson, ; Antherieu et al , ). AhR agonists transcriptionally induce target genes, CYP1A1 and CYP1A2 , in both hepatocytes (Pastorkova et al , ) and intestinal cells (LS180) (Kubesova et al , ). As shown in Fig C (top panel) (see Materials and Methods, Table ), in LS180 cells, FKK5 and FKK6 did not induce CYP1A1 mRNA.…”

Section: Resultsmentioning

confidence: 99%

Targeting the pregnane X receptor using microbial metabolite mimicry

et al. 2020

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The human PXR (pregnane X receptor), a master regulator of drug metabolism, has essential roles in intestinal homeostasis and abrogating inflammation. Existing PXR ligands have substantial off‐target toxicity. Based on prior work that established microbial (indole) metabolites as PXR ligands, we proposed microbial metabolite mimicry as a novel strategy for drug discovery that allows exploiting previously unexplored parts of chemical space. Here, we report functionalized indole derivatives as first‐in‐class non‐cytotoxic PXR agonists as a proof of concept for microbial metabolite mimicry. The lead compound, FKK6 (Felix Kopp Kortagere 6), binds directly to PXR protein in solution, induces PXR‐specific target gene expression in cells, human organoids, and mice. FKK6 significantly represses pro‐inflammatory cytokine production cells and abrogates inflammation in mice expressing the human PXR gene. The development of FKK6 demonstrates for the first time that microbial metabolite mimicry is a viable strategy for drug discovery and opens the door to underexploited regions of chemical space.

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Section: Resultsmentioning

confidence: 99%

Targeting the pregnane X receptor using microbial metabolite mimicry

et al. 2020

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“…In the present review, we are focusing on some articles concerning "Casiopeínas-like" that convey an innovative approach. Casiopeínas-like compounds contain Cu and either phen or bipy ligands, and the modification comes in the secondary ligand [66,[142][143][144]. Some homoleptic compounds have been synthesized containing terpyridine derivatives such as [Cu(bitpy) 2 ](ClO 4 ) 2 , and heteroleptic ones such as [Cu(bitpy)(phen)](NO 3 ) 2 .…”

Section: Casiopeínas-like Compoundsmentioning

confidence: 99%

The Importance of Being Casiopeina as Polypharmacologycal Profile (Mixed Chelate–Copper (II) Complexes and Their In Vitro and In Vivo Activities)

Aguilar-Jiménez,

Espinoza-Guillén,

Resendiz-Acevedo

et al. 2023

Inorganics

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In this review, we present a timeline that shows the origin of mixed chelate copper (II) complexes, registered as Mark Title Casiopeínas®, as the first copper (II) compounds proposed as anticancer drugs in 1988 and 1992. In the late twentieth century, the use of essential metals as anticancer agents was not even considered, except for their antifungal or antibacterial effects; also, copper, as gold salts, was used for arthritis problems. The use of essential metals as anticancer drugs to diminish the secondary toxic effects of Cisplatin was our driving force: to find less toxic and even more economical compounds under the rational design of metal chelate complexes. Due to their chemical properties, copper compounds were the choice to continue anticancer drug development. In this order of ideas, the rational designs of mixed chelate–copper (II) complexes (Casiopeínas, (Cas) homoleptic or heteroleptic, depending on the nature of the secondary ligand) were synthesized and fully characterized. In the search for new, more effective, and less toxic drugs, Casiopeína® (Cas) emerged as a family of approximately 100 compounds synthesized from coordinated Cu(II) complexes with proven antineoplastic potential through cytotoxic action. The Cas have the general formula [Cu(N–N)(N–O)]NO3 and [Cu(N–N)(O–O)]NO3, where N–N is an aromatic substituted diimine (1,10-phenanthroline or 2,2′-bipyridine), and the oxygen donor (O–O) is acetylacetonate or salicylaldehyde. Lately, some similar compounds have been developed by other research groups considering a similar hypothesis after Casiopeína’s discoveries had been published, as described herein. As an example of translational medicine criteria, we have covered each step of the established normative process for drug development, and consequently, one of the molecules (Casiopeína III ia (CasIIIia)) has reached the clinical phase I. For these copper compounds, other activities, such as antibacterial, antiparasitic and antiviral, have been discovered.

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“…HepaRG cells simulate hepatocytes in that PXR ligands can also induce target genes in similar but not identical manner [19][20][21] . AhR agonists transcriptionally induce target genes, CYP1A1 and CYP1A2, in both hepatocytes 22 and intestinal cells (LS180) 23 . As shown in Fig.…”

Section: Characterization Of Fkk Compound(s) Gene Expression Assay Prmentioning

confidence: 99%

Targeting the Pregnane X Receptor Using Microbial Metabolite Mimicry

Dvořák

Kopp

Costello

et al. 2019

Preprint

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The human pregnane X receptor (PXR), a master regulator of drug metabolism, has important roles in intestinal homeostasis and abrogating inflammation. Existing PXR ligands have substantial off-target toxicity. Based on prior work that established microbial (indole) metabolites as PXR ligands, we proposed microbial metabolite mimicry as a novel strategy for drug discovery that allows to exploit previously unexplored parts of chemical space. Here we report functionalized indole-derivatives as firstin-class PXR selective non-cytotoxic agonists, as a proof-of-concept for microbial metabolite mimicry.The lead compound, FKK6, binds directly to PXR protein in solution, induces PXR specific target gene expression in, cells, human organoids, and mice. FKK6 significantly represses pro-inflammatory cytokine production cells and abrogates inflammation in humanized mice. The development of FKK6 demonstrates for the first time that microbial metabolite mimicry is a viable strategy for drug discovery and opens the door to mine underexploited regions of chemical space.

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Mixed-ligand copper(II) complexes activate aryl hydrocarbon receptor AhR and induce CYP1A genes expression in human hepatocytes and human cell lines

Cited by 6 publications

References 31 publications

Targeting the pregnane X receptor using microbial metabolite mimicry

Targeting the pregnane X receptor using microbial metabolite mimicry

The Importance of Being Casiopeina as Polypharmacologycal Profile (Mixed Chelate–Copper (II) Complexes and Their In Vitro and In Vivo Activities)

Targeting the Pregnane X Receptor Using Microbial Metabolite Mimicry

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