The chemosensitizing agent lubeluzole binds calmodulin and inhibits Ca2+/calmodulin-dependent kinase II

Claudio Bruno, Maria Maddalena Cavalluzzi, Maria Rosaria Rusciano, Angelo Lovece, Antonio Carrieri, Riccardo Pracella, Giulia Giannuzzi, Lorenzo Polimeno, Maurizio Viale, Maddalena Illario, Carlo Franchini, Giovanni Lentini

Research output: Contribution to journalArticlepeer-review


An affinity capillary electrophoresis (ACE) method to estimate apparent dissociation constants between bovine brain calmodulin (CaM) and non-peptidic ligands was developed. The method was validated reproducing the dissociation constants of a number of well-known CaM ligands. In particular, the potent antagonist 125-C9 was ad hoc synthesized through an improved synthetic procedure. The ACE method was successfully applied to verify CaM affinity for lubeluzole, a well-known neuroprotective agent recently proved useful to potentiate the activity of anti-cancer drugs. Lubeluzole was slightly less potent than 125-C9 (Kd Combining double low line 2.9 ± 0.7 and 0.47 ± 0.06 1/4M, respectively) and displayed Ca2+/calmodulin-dependent kinase II (CaMKII) inhibition (IC50 Combining double low line 40 ± 1 1/4M). Possible binding modes of lubeluzole to CaM were explored by docking studies based on the X-ray crystal structures of several trifluoperazine-CaM complexes. An estimated dissociation constant in good agreement with the experimental one was found and the main aminoacidic residues and interactions contributing to complex formation were highlighted. The possibility that interference with Ca2+ pathways may contribute to the previously observed chemosensitizing effects of lubeluzole on human ovarian adenocarcinoma and lung carcinoma cells are discussed.

Original languageEnglish
Pages (from-to)36-45
Number of pages10
JournalEuropean Journal of Medicinal Chemistry
Publication statusPublished - Jun 30 2016


  • Affinity capillary electrophoresis
  • Anti-cancer activity
  • Calmodulin
  • Docking
  • Human carcinoma cells
  • Lubeluzole
  • Voltage-gated sodium channels

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Pharmacology

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