Discovery of benzylisothioureas as potent divalent metal transporter 1 (DMT1) inhibitors

Zhang, Zaihui; Vishnumurthy, Kodumuru; Sviridov, Serguei; Liu, Shifeng; Chafeev, Mikhail; Chowdhury, Sultan; Chakka, Nagasree; Sun, Jing; Gauthier, Simon J.; Mattice, Maryanne; Ratkay, Laszlo G.; Kwan, Rainbow; Thompson, Jay; Cutts, Alison J; Fu, Jinmin; Kamboj, Rajender K.; Goldberg, Y. Paul; Cadieux, Jay A.

doi:10.1016/j.bmcl.2012.05.129

Cited by 25 publications

(34 citation statements)

References 23 publications

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“…The compound isothiourea 7, is structurally related to a benzylisothiourea (compound 6 in Fig. 1A) that has been shown to act as a DMT1 inhibitor [17]. Hence, our results suggest that substitution of the aromatic ring of compound 6 ( Fig.…”

Section: Discussionmentioning

confidence: 74%

“…The selected references were three pyridino-pyrazoles (compounds 1-3 [16]) and three aromatic bis-thioamidines (compounds 4-6 [17]) as shown in Fig. 1A.…”

Section: Ligand-based Virtual Screening and Compound Testingmentioning

confidence: 99%

“…Moreover, two small-molecule compounds were reported to specifically inhibit DMT1-mediated iron uptake [15]. More recently, a series of benzylisothiourea and pyrazole derived-compounds were shown to act as potent DMT1 inhibitors [16,17]. However there is scarce information available about the mechanisms of action of these small-molecule compounds on DMT1 transport activity.…”

Section: Introductionmentioning

confidence: 97%

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Discovery and characterization of a novel non-competitive inhibitor of the divalent metal transporter DMT1/SLC11A2

Montalbetti

Simonin

et al. 2015

Biochemical Pharmacology

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Section: Discussionmentioning

confidence: 74%

“…The selected references were three pyridino-pyrazoles (compounds 1-3 [16]) and three aromatic bis-thioamidines (compounds 4-6 [17]) as shown in Fig. 1A.…”

Section: Ligand-based Virtual Screening and Compound Testingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

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Discovery and characterization of a novel non-competitive inhibitor of the divalent metal transporter DMT1/SLC11A2

Montalbetti

Simonin

et al. 2015

Biochemical Pharmacology

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“…These results demonstrate the importance of DMT1 in iron-overload disorders and provides good rationale to target DMT1 in anemic iron-overload disorders. Similar to HIF2α, compounds have been identified that inhibit DMT1 function (49,50), and thus it may be possible to specifically inhibit DMT1 as a novel treatment modality in iron-overload disorders.…”

Section: (E) Dmt1mentioning

confidence: 99%

Intestinal HIF2α promotes tissue-iron accumulation in disorders of iron overload with anemia

Anderson¹,

Taylor²,

Xue³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Several distinct congenital disorders can lead to tissue-iron overload with anemia. Repeated blood transfusions are one of the major causes of iron overload in several of these disorders, including β-thalassemia major, which is characterized by a defective β-globin gene. In this state, hyperabsorption of iron is also observed and can significantly contribute to iron overload. In β-thalassemia intermedia, which does not require blood transfusion for survival, hyperabsorption of iron is the leading cause of iron overload. The mechanism of increased iron absorption in β-thalassemia is unclear. We definitively demonstrate, using genetic mouse models, that intestinal hypoxia-inducible factor-2α (HIF2α) and divalent metal transporter-1 (DMT1) are activated early in the pathogenesis of β-thalassemia and are essential for excess iron accumulation in mouse models of β-thalassemia. Moreover, thalassemic mice with established iron overload had significant improvement in tissue-iron levels and anemia following disruption of intestinal HIF2α. In addition to repeated blood transfusions and increased iron absorption, chronic hemolysis is the major cause of tissue-iron accumulation in anemic iron-overload disorders caused by hemolytic anemia. Mechanistic studies in a hemolytic anemia mouse model demonstrated that loss of intestinal HIF2α/DMT1 signaling led to decreased tissue-iron accumulation in the liver without worsening the anemia. These data demonstrate that dysregulation of intestinal hypoxia and HIF2α signaling is critical for progressive iron overload in β-thalassemia and may be a novel therapeutic target in several anemic iron-overload disorders.

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“…20 Both groups used similar assays based on the property of Fe 2+ to quench the fluorescence signal of Calcein. In addition, there are commonly use nonfluorescent methods to measure intracellular iron such as atomic absoption spectroscopy 30 and ferrozine-based colorimetric assay, 31 which could be compatible with HTS.…”

Section: Discussionmentioning

confidence: 99%

Development and Validation of a Fast and Homogeneous Cell-Based Fluorescence Screening Assay for Divalent Metal Transporter 1 (DMT1/SLC11A2) Using the FLIPR Tetra

et al. 2014

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Divalent metal ion transporter 1 (DMT1) is a proton-coupled Fe 2+ transporter that is essential for iron uptake in enterocytes and for transferrin-associated endosomal iron transport in many other cell types. DMT1 dysfunction is associated with several diseases such as iron overload disorders and neurodegenerative diseases. The main objective of the present work is to develop and validate a fluorescence-based screening assay for DMT1 modulators. We found that Fe 2+ or Cd 2+ influx could be reliably monitored in calcium 5-loaded DMT1-expressing HEK293 cells using the FLIPR Tetra fluorescence microplate reader. DMT1-mediated metal transport shows saturation kinetics depending on the extracellular substrate concentration, with a K 0.5 value of 1.4 µM and 3.5 µM for Fe 2+ and Cd 2+ , respectively. In addition, Cd 2+ was used as a substrate for DMT1, and we find a K i value of 2.1 µM for a compound (2-(3-carbamimidoylsulfanylmethyl-benzyl)-isothiourea) belonging to the benzylisothioureas family, which has been identified as a DMT1 inhibitor. The optimized screening method using this compound as a reference demonstrated a Z′ factor of 0.51. In summary, we developed and validated a sensitive and reproducible cell-based fluorescence assay suitable for the identification of compounds that specifically modulate DMT1 transport activity.

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Discovery of benzylisothioureas as potent divalent metal transporter 1 (DMT1) inhibitors

Cited by 25 publications

References 23 publications

Discovery and characterization of a novel non-competitive inhibitor of the divalent metal transporter DMT1/SLC11A2

Discovery and characterization of a novel non-competitive inhibitor of the divalent metal transporter DMT1/SLC11A2

Intestinal HIF2α promotes tissue-iron accumulation in disorders of iron overload with anemia

Development and Validation of a Fast and Homogeneous Cell-Based Fluorescence Screening Assay for Divalent Metal Transporter 1 (DMT1/SLC11A2) Using the FLIPR Tetra

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