2. Academic Validation
  3. A Comprehensive In Vitro Characterization of a New Class of Indole-Based Compounds Developed as Selective Haspin Inhibitors

A Comprehensive In Vitro Characterization of a New Class of Indole-Based Compounds Developed as Selective Haspin Inhibitors

  • J Med Chem. 2024 Jul 22. doi: 10.1021/acs.jmedchem.4c00718.
Vincenzo Vestuto 1,  Tania Ciaglia 1,  Simona Musella 1,  Veronica Di Sarno 1,  Gerardina Smaldone 1,  Francesca Di Matteo 1,  Maria Carmina Scala 1,  Valeria Napolitano 1,  Maria Rosaria Miranda 1,  Giuseppina Amodio 2,  Sara Novi 1,  Giacomo Pepe 1,  Manuela Giovanna Basilicata 3,  Erica Gazzillo 1,  Simona Pace 1,  Isabel M Gomez-Monterrey 4,  Marina Sala 1,  Giuseppe Bifulco 1,  Mario Felice Tecce 1,  Pietro Campiglia 1,  Carmine Ostacolo 1,  Gianluigi Lauro 1,  Michele Manfra 5,  Alessia Bertamino 1
Affiliations

Affiliations

  • 1 Department of Pharmacy, University of Salerno, Via G. Paolo II 132 , Salerno , Fisciano 84084, Italy.
  • 2 Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana″, University of Salerno, Salerno , Baronissi 84034, Italy.
  • 3 Department of Advanced Medical and Surgical Science, University of Campania "Luigi Vanvitelli", P.zza L. Miraglia 2, Naples 80138, Italy.
  • 4 Department of Pharmacy, University Federico II of Naples, Via D. Montesano 49 , Naples 80131, Italy.
  • 5 Department of Science, University of Basilicata, Via dell'Ateneo Lucano 10 , Potenza 85100, Italy.
PMID: 39038808 DOI: 10.1021/acs.jmedchem.4c00718
Abstract

Haspin is an emerging, but rather unexplored, divergent kinase involved in tumor growth by regulating the mitotic phase. In this paper, the in-silico design, synthesis, and biological characterization of a new series of substituted indoles acting as potent Haspin inhibitors are reported. The synthesized derivatives have been evaluated by FRET analysis, showing very potent Haspin inhibition. Then, a comprehensive in-cell investigation highlighted compounds 47 and 60 as the most promising inhibitors. These compounds were challenged for their synergic activity with paclitaxel in 2D and 3D cellular models, demonstrating a twofold improvement of the paclitaxel antitumor activity. Compound 60 also showed remarkable selectivity when tested in a panel of 70 diverse kinases. Finally, in-silico studies provided new insight about the chemical requirements useful to develop new Haspin inhibitors. Biological results, together with the drug-likeness profile of 47 and 60, make these derivatives deserving further studies.

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