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Designed by linking an FRB-binding moiety to a TORKI structure, RapaLink-1 is able to overcome resistance in cancer cells that harbor mutations in either the FRB or kinase domains of mTOR

J Biol Chem (2007) 282(42):3054452

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The resultant accumulation of labile iron intensifies oxidative stress via Fenton chemistry and ultimately renders dopaminergic neurons highly susceptible to ferroptosis ( Cells export iron via the plasma membrane iron exporter protein, FPN1, the sole identified protein responsible for exporting intracellular iron in mammals ( Ceruloplasmin (CP) is a ferroxidase that is mainly found in a GPI-anchored form on astrocytes, converting toxic Fe 2+ to non-toxic Fe 3+ , physically associating with FPN1 to facilitate iron efflux from central nervous system cells, and inhibiting Fe 2+ -mediated lipid peroxidation by reducing the presence of highly reactive Fe 2+ ( In vitro experiments demonstrated that functionally impaired CP fails to effectively oxidize Fe 2+ , leading to iron ion retention in neuronal cells and promotion of ferroptosis ( Iron regulatory proteins (IRPs), bind to iron-responsive elements (IREs) in the 5 untranslated region (UTR) of mRNAs encoding ferritin and FPN1 to inhibit their translation, while binding to IREs in the 3 UTR of TfR1 and DMT1 mRNAs to stabilize these transcripts, thereby adjusting iron storage, export, and uptake ( 2.1.3 The dual role of NM in iron homeostasis and PD pathology NM-containing neurons in the SNpc and the locus coeruleus are among the most vulnerable and prominently degenerated cell types in PD