A Novel Family of Lysosomotropic Tetracyclic Compounds for Treating Leukemia
Carbó, José María (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Cornet-Masana, Josep Maria (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Cuesta-Casanovas, Laia (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Delgado-Martínez, Jennifer (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Banús, Antònia (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Clément-Demange, Lise (Leukos Biotech (Barcelona))
Serra, Carme (Institut de Química Avançada de Catalunya)
Catena, Juanlo (Institut de Química Avançada de Catalunya)
Llebaria, Amadeu (Institut de Química Avançada de Catalunya)
Esteve Reyner, Jordi (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Risueño, Ruth M (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Universitat Autònoma de Barcelona

Data:	2023
Resum:	In spite of the recent expansion of the therapeutic landscape for acute myeloid leukemia (AML), resistance mechanisms and relapsed disease still pose a serious barrier to achieve curation for most patients. Considering the high inter- and intrapatient heterogeneity, disruptive therapeutic approaches are expected to provide a clinical solution for this unmet need. An in silico drug discovery program identified a new family of lysosome- and mitochondria-targeting compounds that specifically eradicate leukemia ex vivo and in vivo in relevant preclinical models by inducing both mitochondrial damage and apoptosis, and the simultaneous lysosomal membrane leakiness. Moreover, the compounds are effective in a wide panel of cancer cell lines, as their mechanism of action targets a common neoplastic feature. These compounds possess adequate pharmacological properties rendering them promising drug candidates for AML and unrelated neoplasias, and support their further clinical development. 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 Ca 2+ -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.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Apoptosis ; Autophagy ; Drug discovery ; Leukemia ; Lysosome ; New chemical entity
Publicat a:	Cancers, Vol. 15 (march 2023) , ISSN 2072-6694

DOI: 10.3390/cancers15061912
PMID: 36980800

19 p, 2.6 MB

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Documents de recerca > Documents dels grups de recerca de la UAB > Centres i grups de recerca (producció científica) > Ciències de la salut i biociències > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP) > Institut de Recerca contra la Leucèmia Josep Carreras
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