e58d5031eebd829823817442ab81596b pmc_10047683.pdf b6e6c243d7f8cd964eae975f632258f52a12294f pmc_10047683.pdf d308b21593bfadb40ed53768145716e5b9280c878c9f3f049ff3f167a3c5f5ab pmc_10047683.pdf Title: A Novel Family of Lysosomotropic Tetracyclic Compounds for Treating Leukemia Subject: Acute myeloid leukemia (AML) is a heterogeneous hematological cancer characterized by poor prognosis and frequent relapses. Aside from specific mutation-related changes, in AML, the overall function of lysosomes and mitochondria is drastically altered to fulfill the elevated biomass and bioenergetic demands. On the basis of previous results, in silico drug discovery screening was used to identify a new family of lysosome-/mitochondria-targeting compounds. These novel tetracyclic hits, with a cationic amphiphilic structure, specifically eradicate leukemic cells by inducing both mitochondrial damage and apoptosis, and simultaneous lysosomal membrane leakiness. Lysosomal leakiness does not only elicit canonical lysosome-dependent cell death, but also activates the terminal differentiation of AML cells through the Ca2+–TFEB–MYC signaling axis. In addition to being an effective monotherapy, its combination with the chemotherapeutic arsenic trioxide (ATO) used in other types of leukemia is highly synergistic in AML cells, widening the therapeutic window of the treatment. Moreover, the compounds are effective in a wide panel of cancer cell lines and possess adequate pharmacological properties rendering them promising drug candidates for the treatment of AML and other neoplasias. Keywords: leukemia; drug discovery; autophagy; apoptosis; new chemical entity; lysosome Author: José M. Carbó, Josep M. Cornet-Masana, Laia Cuesta-Casanovas, Jennifer Delgado-Martínez, Antònia Banús-Mulet, Lise Clément-Demange, Carme Serra, Juanlo Catena, Amadeu Llebaria, Jordi Esteve and Ruth M. Risueño Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Thu Mar 23 03:24:52 2023 CET ModDate: Thu Mar 23 03:31:15 2023 CET Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 19 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 2685285 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- LKRQDW+VnURWPalladioL-Bold Type 1 Custom yes yes no 10 0 SLLMPE+VnURWPalladioL Type 1 Custom yes yes no 15 0 GCCGDI+URWPalladioL-Bold Type 1 Custom yes yes no 19 0 BQWSYY+URWPalladioL-Roma Type 1 Custom yes yes no 24 0 KAAGXS+URWPalladioL-Ital Type 1 Custom yes yes no 28 0 LCJEVJ+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 47 0 VYVZGZ+CMSY10 Type 1 Builtin yes yes no 72 0 ZXDKIP+EURM10 Type 1 Builtin yes yes no 76 0 BCDEEE+PalatinoLinotype-Bold TrueType WinAnsi yes yes no 94 0 BCDFEE+PalatinoLinotype-Roman 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Title: Introduction Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@44c8afef Item: Title: Materials and Methods Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7b69c6ba Children: Item: Title: Primary Samples Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@46daef40 Item: Title: Chemoinformatic Screening Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@12f41634 Item: Title: Cytotoxicity Assays Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@13c27452 Item: Title: In Vivo Studies Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@262b2c86 Item: Title: Lysosomal Studies Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@371a67ec Item: Title: Autophagy Analysis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@5ed828d Item: Title: TFEB Activation Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@50d0686 Item: Title: Mitochondrial Analysis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7a3d45bd Item: Title: ADMET and PK Profiles Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1e7c7811 Item: Title: Synergy Calculation Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77ec78b9 Item: Title: Results Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1a3869f4 Children: Item: Title: Identification of Novel Antileukemic Molecules Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@a38d7a3 Item: Title: In Vivo Effectivity of EDK-87/EDK-88 Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77f99a05 Item: Title: Dual Targeting of Lysosomes and Mitochondria Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@63440df3 Item: Title: Synergism with Arsenic Trioxide Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@3aeaafa6 Item: Title: Pan-Cancer Effectivity of EDK-87/EDK-88 Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@76a3e297 Item: Title: Pharmacokinetic and ADMET Profiles Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4d3167f4 Item: Title: Discussion Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@ed9d034 Item: Title: Conclusions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@6121c9d6 Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@87f383f Info: Title: A Novel Family of Lysosomotropic Tetracyclic Compounds for Treating Leukemia Author: José M. Carbó, Josep M. Cornet-Masana, Laia Cuesta-Casanovas, Jennifer Delgado-Martínez, Antònia Banús-Mulet, Lise Clément-Demange, Carme Serra, Juanlo Catena, Amadeu Llebaria, Jordi Esteve and Ruth M. Risueño Subject: Acute myeloid leukemia (AML) is a heterogeneous hematological cancer characterized by poor prognosis and frequent relapses. Aside from specific mutation-related changes, in AML, the overall function of lysosomes and mitochondria is drastically altered to fulfill the elevated biomass and bioenergetic demands. On the basis of previous results, in silico drug discovery screening was used to identify a new family of lysosome-/mitochondria-targeting compounds. These novel tetracyclic hits, with a cationic amphiphilic structure, specifically eradicate leukemic cells by inducing both mitochondrial damage and apoptosis, and simultaneous lysosomal membrane leakiness. Lysosomal leakiness does not only elicit canonical lysosome-dependent cell death, but also activates the terminal differentiation of AML cells through the Ca2+ TFEB MYC signaling axis. In addition to being an effective monotherapy, its combination with the chemotherapeutic arsenic trioxide (ATO) used in other types of leukemia is highly synergistic in AML cells, widening the therapeutic window of the treatment. Moreover, the compounds are effective in a wide panel of cancer cell lines and possess adequate pharmacological properties rendering them promising drug candidates for the treatment of AML and other neoplasias. 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