Pyrazolyl-pyrimidones inhibit the function of human solute carrier protein SLC11A2 (hDMT1) by metal chelation

Poirier, Marion; Pujol‐Giménez, Jonai; Manatschal, Cristina; Bühlmann, Sven; Embaby, Ahmed; Javor, Sacha; Hediger, Matthias A.; Reymond, Jean‐Louis

doi:10.1039/d0md00085j

Cited by 5 publications

(6 citation statements)

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“…The relative positioning of the two amines in rac ‐ 3 suggests that the observed iron uptake inhibition might reflect metal chelation as reported recently for pyrazolyl‐pyrimidones. [25] To exclude this possibility, we performed a calcein competition assay, where the quenching of calcein fluorescence indicates the presence of free Fe 2+ . In contrast to the positive control bipyridine, we could not detect any significant level of iron chelation by rac ‐ 3 (Figure 3 f).…”

Section: Resultsmentioning

confidence: 99%

“…We used a concentration of 10 μM screening compound, which we judged sufficiently low to avoid non-specific effects on cells but high enough to indicate even a weak inhibition, as described earlier. [25] The assay revealed 162 compounds with only weak activity (15-25 %), which were then retested at higher concentration (50 μM) to observe a stronger effect for confirmation. By repurchasing, purification and retesting, we were able to confirm the activity of trifluoromethylsulfone 1 a (IC 50 = 64.5 � 1.1 μM) corresponding to a ligand efficiency of LE = 0.42 kcal .…”

Section: Activity Screeningmentioning

confidence: 99%

“…[20][21][22] Although little information is available on their structure, divalent metal transporters possess well defined pockets that should be suitable for inhibition by small molecules, as recently shown by the structural characterization of a competitive inhibitor of DMT1 in complex with a bacterial analog of the transporter. [23,24] In view of our previous difficulties in identifying DMT1 inhibitors caused by interfering metal chelation [25] and the almost complete absence of known inhibitors for such transporters, we set out to identify small molecule inhibitors using a fragment-based drug discovery approach. Fragmentbased drug discovery consists in testing a small number of structurally diverse fragments, defined as rigid small molecules with few functional groups (Congreve's rule of 3: MW � 300 Da, H-bond acceptor atoms � 3, H-bond donor atoms � 3, rotatable bonds � 3, polar surface area � 60 Å 2 ), for weak target interaction to identify initial hits which can later be optimized for activity.…”

Section: Introductionmentioning

confidence: 99%

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Inhibitors of Human Divalent Metal Transporters DMT1 (SLC11A2) and ZIP8 (SLC39A8) from a GDB‐17 Fragment Library

et al. 2021

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Dedicated to the memory of Prof. François DiederichSolute carrier proteins (SLCs) are membrane proteins controlling fluxes across biological membranes and represent an emerging class of drug targets. Here we searched for inhibitors of divalent metal transporters in a library of 1,676 commercially available 3D-shaped fragment-like molecules from the generated database GDB-17, which lists all possible organic molecules up to 17 atoms of C, N, O, S and halogen following simple criteria for chemical stability and synthetic feasibility. While screening against DMT1 (SLC11A2), an iron transporter associated with hemochromatosis and for which only very few inhibitors are known, only yielded two weak inhibitors, our approach led to the discovery of the first inhibitor of ZIP8 (SLC39A8), a zinc transporter associated with manganese homeostasis and osteoarthritis but with no previously reported pharmacology, demonstrating that this target is druggable.

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Section: Resultsmentioning

confidence: 99%

Section: Activity Screeningmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Inhibitors of Human Divalent Metal Transporters DMT1 (SLC11A2) and ZIP8 (SLC39A8) from a GDB‐17 Fragment Library

et al. 2021

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“…Accumulation of radiolabelled Fe 55 in transiently transfected HEK293T was performed as previously described ( Poirier et al, 2020 ). Accumulated Intracellular 55 Fe was measured with the MicroBeta 2 microplate counter for radiometric and luminescence detection (PerkinElmer).…”

Section: Methodsmentioning

confidence: 99%

The Allelic Variant A391T of Metal Ion Transporter ZIP8 (SLC39A8) Leads to Hypotension and Enhanced Insulin Resistance

et al. 2022

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The metal ion transporter ZIP8 (SLC39A8) mediates cellular uptake of vital divalent metal ions. Genome-wide association studies (GWAS) showed that the single-nucleotide polymorphism (SNP) variant A391T (rs13107325) is associated with numerous human traits, including reduced arterial blood pressure, increased body mass index and hyperlipidemia. We analyzed in vitro the transport properties of mutant ZIP8 A391T and investigated in vivo in mice the physiological effects of this polymorphism. In vitro, the intrinsic transport properties of mutant ZIP8 were similar to those of wild type ZIP8, but cellular uptake of zinc, cadmium and iron was attenuated due to reduced ZIP8 plasma membrane expression. We then generated the ZIP8 A393T mice (ZIP8KI) that carry the corresponding polymorphism and characterized their phenotype. We observed lower protein expression in lung and kidney membrane extracts in ZIP8KI mice. The ZIP8KI mice exhibited striking changes in metal ion composition of the tissues, including cobalt, palladium, mercury and platinum. In agreement with GWAS, ZIP8KI mice showed reduced arterial blood pressure. Body weight and plasma lipid composition remained unchanged, although these features were reported to be increased in GWAS. ZIP8KI mice also exhibited remarkable insulin resistance and were protected from elevated blood glucose when challenged by dietary sucrose supplementation. We showed that increased hepatic insulin receptor expression and decreased ZnT8 (slc30a8) metal ion transporter mRNA expression are associated with this phenotypic change. In conclusion, our data reveal that ZIP8 plays an important role in blood pressure regulation and glucose homeostasis.

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“…This revealed the upregulation of genes involved in iron-homeostasis, further confirming the finding of Poirier et al that pyrazolylpyrimidones act by via metal chelation. 28 This was further verified in a 2D-checkerboard assay by iron supplementation to the growth medium displaying rescue of bacterial growth from the toxicity of pyrazolylpyrimidinones, confirming the perturbation of Fe-homeostasis as a MoA. This highlights the need to include such metal chelating groups among pan-assay interference compounds.…”

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confidence: 99%

Innovation Experiences from Africa-Led Drug Discovery at the Holistic Drug Discovery and Development (H3D) Centre

Singh

Mambwe

Korkor

et al. 2022

ACS Med. Chem. Lett.

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As the so-called “next frontier” in global economic terms, Africa’s disease burden continues to choke and cripple economic growth across the continent. The highest burden is attributable to malaria and tuberculosis (TB), which also remain among the deadliest infectious diseases affecting mankind the world over (Malaria, 627,000 deaths; TB, 1.5 million deaths, in 2020). In achieving self-determination with respect to the health needs of all who live on the continent, Africa must align with global north efforts and be a source of health innovation. This will in part require the creation of an ecosystem of innovative pharmaceutical R&D and expanding it across the continent by scaling up through sustained performance and excellence. To this end, the Holistic Drug Discovery and Development (H3D) Centre at University of Cape Town in South Africa has risen to this challenge. Here, we highlight the innovation experiences gained at H3D, covering the advances made in our quest to contribute to a global pipeline of therapeutic interventions against malaria and TB. We discuss selected chemical series starting from their identification, structure–activity relationships, mode of action, safety, proof-of-concept studies, and lessons learned.

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Pyrazolyl-pyrimidones inhibit the function of human solute carrier protein SLC11A2 (hDMT1) by metal chelation

Abstract: Activity optimization of a pyrazolyl-pyrimidone against the iron transporter SLC11A2 (hDMT1) and mechanistic studies revealed that this class of inhibitors act by metal chelation.

Cited by 5 publications

References 42 publications

Inhibitors of Human Divalent Metal Transporters DMT1 (SLC11A2) and ZIP8 (SLC39A8) from a GDB‐17 Fragment Library

Inhibitors of Human Divalent Metal Transporters DMT1 (SLC11A2) and ZIP8 (SLC39A8) from a GDB‐17 Fragment Library

The Allelic Variant A391T of Metal Ion Transporter ZIP8 (SLC39A8) Leads to Hypotension and Enhanced Insulin Resistance

Innovation Experiences from Africa-Led Drug Discovery at the Holistic Drug Discovery and Development (H3D) Centre

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