- DMT1 Inhibitors Kill Cancer Stem Cells by Blocking Lysosomal Iron Translocation
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Cancer stem cells (CSC) constitute a cell subpopulation in solid tumors that is responsible for resistance to conventional chemotherapy, metastasis and cancer relapse. The natural product Salinomycin can selectively target this cell niche by directly interacting with lysosomal iron, taking advantage of upregulated iron homeostasis in CSC. Here, inhibitors of the divalent metal transporter 1 (DMT1) have been identified that selectively target CSC by blocking lysosomal iron translocation. This leads to lysosomal iron accumulation, production of reactive oxygen species and cell death with features of ferroptosis. DMT1 inhibitors selectively target CSC in primary cancer cells and circulating tumor cells, demonstrating the physiological relevance of this strategy. Taken together, this opens up opportunities to tackle unmet needs in anti-cancer therapy.
- Turcu, Andreea L.,Versini, Antoine,Khene, Nadjib,Gaillet, Christine,Ca?eque, Tatiana,Müller, Sebastian,Rodriguez, Rapha?l
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p. 7369 - 7373
(2020/06/02)
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- Discovery of benzylisothioureas as potent divalent metal transporter 1 (DMT1) inhibitors
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Inhibition of intestinal brush border DMT1 offers a novel therapeutic approach to the prevention and treatment of disorders of iron overload. Several series of diaryl and tricyclic benzylisothiourea compounds as novel and potent DMT1 inhibitors were discovered from the original hit compound 1. These compounds demonstrated in vitro potency against DMT1, desirable cell permeability properties and a dose-dependent inhibition of iron uptake in an acute rat model of iron hyperabsorption. Tricyclic compounds increased the in vitro potency by up to 16-fold versus the original hit. Diaryl compounds 6b and 14a demonstrated significant iron absorption inhibition in vivo with both 25 and 50 mg/kg doses. The diaryl and tricyclic compounds described in this report represent promising structural templates for further optimization.
- Zhang, Zaihui,Kodumuru, Vishnumurthy,Sviridov, Serguei,Liu, Shifeng,Chafeev, Mikhail,Chowdhury, Sultan,Chakka, Nagasree,Sun, Jianyu,Gauthier, Simon J.,Mattice, Maryanne,Ratkay, Laszlo G.,Kwan, Rainbow,Thompson, Jay,Cutts, Alison Brownlie,Fu, Jianmin,Kamboj, Rajender,Goldberg, Y. Paul,Cadieux, Jay A.
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p. 5108 - 5113
(2012/08/28)
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- BIARYL AND BIHETEROARYL COMPOUNDS USEFUL IN TREATING IRON DISORDERS
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This invention is directed to compounds of formula (I): wherein m, n, R1, R2 and R3 are as defined herein, as a stereoisomer, enantiomer, tautomer thereof or mixtures thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof, for the treatment of iron disorders. This invention is also directed to pharmaceutical compositions comprising the compounds and methods of using the compounds to treat iron disorders.
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Page/Page column 49
(2008/12/07)
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