2. Academic Validation
  3. Identification of an indol-based multi-target kinase inhibitor through phenotype screening and target fishing using inverse virtual screening approach

Identification of an indol-based multi-target kinase inhibitor through phenotype screening and target fishing using inverse virtual screening approach

  • Eur J Med Chem. 2019 Apr 1:167:61-75. doi: 10.1016/j.ejmech.2019.01.066.
Carmine Ostacolo 1,  Veronica Di Sarno 2,  Gianluigi Lauro 2,  Giacomo Pepe 2,  Simona Musella 2,  Tania Ciaglia 2,  Vincenzo Vestuto 2,  Giuseppina Autore 2,  Giuseppe Bifulco 2,  Stefania Marzocco 2,  Pietro Campiglia 2,  Isabel M Gomez-Monterrey 3,  Alessia Bertamino 4
Affiliations

Affiliations

  • 1 Department of Pharmacy, University of Naples Federico II, Via D. Montesano 49, 80131, Naples, Italy.
  • 2 Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084, Fisciano, SA, Italy.
  • 3 Department of Pharmacy, University of Naples Federico II, Via D. Montesano 49, 80131, Naples, Italy. Electronic address: imgomez@unina.it.
  • 4 Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084, Fisciano, SA, Italy. Electronic address: abertamino@unisa.it.
PMID: 30763817 DOI: 10.1016/j.ejmech.2019.01.066
Abstract

A series of 1,3,5-substituted indole derivatives was prepared to explore the anti-proliferative activity against a panel of human tumour cell lines. A 5-carboxamide derivative (27) emerged as the most potent compound of this series, inhibiting the HeLa cell growth at sub-micromolar concentrations. Target fishing of 27 using a combination of inverse virtual screening (IVS) approach and ligand-based shape similarity study identified the top-ranked targets for 27 as belonging to kinome. These results were further confirmed by in vitro binding assays, leading to the identification of 27 as multi-target kinase inhibitor. The compound 27 was further characterized for its antiproliferative activity by in cell studies, showing a mechanism of action involving modification of the cell cycle, increase in ROS release and Caspase 3-expression and decrease in ERK expression.

Keywords

1,3,5-Substituted indole derivatives; In cell studies; Kinase multi-target inhibitor; Target fishing.

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