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Targeting heme Oxygenase-1 with hybrid compounds to overcome Imatinib resistance in chronic myeloid leukemia cell lines.

Abstract
Heme oxygenase-1 (HO-1) is a cytoprotective enzyme and a survival-enhancing factor in a number of cancers. Chronic myeloid leukemia (CML) is a blood cancer caused by pathological kinase activity of the BCR-ABL protein, currently treated with tyrosine kinase inhibitors (TKIs) such as Imatinib (IM). However, resistance to TKIs persists in a number of patients and HO-1 overexpression has been linked with the induction of chemoresistance in CML. With this in mind, in this study, we designed and synthesized the first series of hybrid compounds obtained by combining the structures of IM, as BCR-ABL inhibitor, with imidazole-based HO-1 inhibitors. We found that many hybrids were able to inhibit the enzymatic activity of both targets and to reduce the viability of CML-IM resistant cells, showing that a single molecular entity may reduce the resistance phenomenon.
AuthorsValeria Sorrenti, Valeria Pittalà, Giuseppe Romeo, Emanuele Amata, Maria Dichiara, Agostino Marrazzo, Rita Turnaturi, Orazio Prezzavento, Ignazio Barbagallo, Luca Vanella, Antonio Rescifina, Giuseppe Floresta, Daniele Tibullo, Francesco Di Raimondo, Sebastiano Intagliata, Loredana Salerno
JournalEuropean journal of medicinal chemistry (Eur J Med Chem) Vol. 158 Pg. 937-950 (Oct 05 2018) ISSN: 1768-3254 [Electronic] France
PMID30261468 (Publication Type: Journal Article)
CopyrightCopyright © 2018 Elsevier Masson SAS. All rights reserved.
Chemical References
  • Antineoplastic Agents
  • Imidazoles
  • Imatinib Mesylate
  • Heme Oxygenase-1
  • Fusion Proteins, bcr-abl
Topics
  • Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
  • Cell Survival (drug effects)
  • Drug Design
  • Drug Resistance, Neoplasm
  • Fusion Proteins, bcr-abl (antagonists & inhibitors, metabolism)
  • Heme Oxygenase-1 (antagonists & inhibitors, metabolism)
  • Humans
  • Imatinib Mesylate (analogs & derivatives, chemical synthesis, pharmacology)
  • Imidazoles (chemical synthesis, chemistry, pharmacology)
  • K562 Cells
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy, metabolism)
  • Molecular Docking Simulation

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