: 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.; Ostacolo, C.; Lauro, G.; Manfra, M.; Bertamino, A.. - 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.
