Chemically stable inhibitors of 14-3-3 protein–protein interactions derived from BV02. (1st January 2019)

• Record Type: Journal Article
• Authors: Iralde-Lorente, Leire; Cau, Ylenia; Clementi, Letizia; Franci, Lorenzo; Tassone, Giusy; Valensin, Daniela; Mori, Mattia; Angelucci, Adriano; Chiariello, Mario; Botta, Maurizio
• Is Part Of: Journal of enzyme inhibition and medicinal chemistry. Volume 34:Number 1(2019)
• Page Start: 657
• Page End: 664
• Publication Date: 2019-01-01
• Subjects: 14-3-3 -- protein–protein interaction -- c-Abl -- leukaemia -- 4-aminoantipyrine; Enzyme inhibitors -- Periodicals; Enzyme Inhibitors -- periodicals; Biochemistry -- periodicals; 572.7
• DOI: 10.1080/14756366.2019.1574779
• Languages: English
• ISSNs: 1475-6366

Abstract

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.