: 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.
A Comprehensive In Vitro Characterization of a New Class of Indole-Based Compounds Developed as Selective Haspin Inhibitors / Vestuto, V., Ciaglia, T., Musella, S., Di Sarno, V., Smaldone, G., Di Matteo, F., Scala, M.C., Napolitano, V., Miranda, M.R., Amodio, G., Novi, S., Pepe, G., Basilicata, M.G., Gazzillo, E., Pace, S., Gomez-Monterrey, I.M., Sala, M., Bifulco, G., Tecce, M.F., Campiglia, P., et al.. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 1520-4804. - 67:15(2024), pp. 12711-12734. [10.1021/acs.jmedchem.4c00718]
A Comprehensive In Vitro Characterization of a New Class of Indole-Based Compounds Developed as Selective Haspin Inhibitors
Gomez-Monterrey I. M.Writing – Review & Editing
;
2024
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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
