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
  • 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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