Chemically stable inhibitors of 14-3-3 protein-protein interactions derived from BV02

J Enzyme Inhib Med Chem. 2019 Dec;34(1):657-664. doi: 10.1080/14756366.2019.1574779.

Abstract

14-3-3 are regulatory proteins that through protein-protein interactions (PPI) with numerous binding partners could be involved in several human diseases, including cancer, neurodegenerative disorders, and pathogens infections. Following our research interest in the development of 14-3-3 PPI inhibitors, here we exploited the privileged 4-aminoantipyrine scaffold in the design and synthesis of some derivatives endowed with antiproliferative activity against K-562 cells, and capable of binding to recombinant 14-3-3σ as evidenced by NMR spectroscopy. The binding mode was further explored by molecular modelling, while coupling confocal microscopy with intensitometric analysis showed that compound 1 was able to promote the nuclear translocation of c-Abl at low micromolar concentrations. Overall, 1 is chemically stable compared to parent 14-3-3 PPI inhibitors, and thus emerged as a confirmed hit for further development.

Keywords: 14-3-3; 4-aminoantipyrine; c-Abl; leukaemia; protein–protein interaction.

MeSH terms

  • 14-3-3 Proteins / antagonists & inhibitors*
  • 14-3-3 Proteins / chemistry
  • 14-3-3 Proteins / metabolism
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Benzamides / chemical synthesis
  • Benzamides / chemistry
  • Benzamides / pharmacology*
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • HeLa Cells
  • Humans
  • K562 Cells
  • Molecular Structure
  • Protein Binding / drug effects
  • Pyrazoles / chemical synthesis
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology*
  • Structure-Activity Relationship

Substances

  • 14-3-3 Proteins
  • Antineoplastic Agents
  • BV02 compound
  • Benzamides
  • Pyrazoles

Grants and funding

This work is supported by the Initial Training Network, funded by the H2020 Marie Curie Actions of the European Commission under Grant Agreement 675179. This work was also supported by the Italian MIUR, through the PRIN (Programmi di Ricerca di Rilevante Interesse Nazionale) Project 2015T778JW_003.