Protein kinases have emerged as crucial targets for cancer therapy over the last decades. Since 2001, 40 and 39 kinase inhibitors have been approved by FDA and EMA, respectively, and the majority are antineoplastic drugs. Morevoer, many candidates are currently in clinical trials. We previously reported a small library of 4-aminoimidazole and 2-aminothiazole derivatives active as Src family kinase (SFK) inhibitors. Starting from these results, we decided to perform an optimization study applying a mix and match strategy to identify a more potent generation of 4-aminoimidazoles. Firstly, a computational study has been performed, then compounds showing the best predicted docking scores were synthesized and screened in a cell-free assay for their SFK inhibitory activity. All the new chemical entities showed IC(50)s in the nanomolar range, with 2-130 fold increased activities compared to the previously reported inhibitors. Finally, the most active compounds have been tested on three cancer cell lines characterized by Src hyperactivation. Compounds 4k and 4l showed an interesting antiproliferative activity on SH-SY5Y neuroblastoma (NB) cell line. In this assay, the compounds resulted more potent than dasatinib, a tyrosine kinase inhibitor approved for the treatment of leukemias and in clinical trials for NB.

Francini, C.m., Musumeci, F., Fallacara, A.l., Botta, L., Molinari, A., Artusi, R., et al. (2018). Optimization of aminoimidazole derivatives as Src family kinase inhibitors. MOLECULES, 23(9), 2369 [10.3390/molecules23092369].

Optimization of aminoimidazole derivatives as Src family kinase inhibitors

Botta L.;
2018-01-01

Abstract

Protein kinases have emerged as crucial targets for cancer therapy over the last decades. Since 2001, 40 and 39 kinase inhibitors have been approved by FDA and EMA, respectively, and the majority are antineoplastic drugs. Morevoer, many candidates are currently in clinical trials. We previously reported a small library of 4-aminoimidazole and 2-aminothiazole derivatives active as Src family kinase (SFK) inhibitors. Starting from these results, we decided to perform an optimization study applying a mix and match strategy to identify a more potent generation of 4-aminoimidazoles. Firstly, a computational study has been performed, then compounds showing the best predicted docking scores were synthesized and screened in a cell-free assay for their SFK inhibitory activity. All the new chemical entities showed IC(50)s in the nanomolar range, with 2-130 fold increased activities compared to the previously reported inhibitors. Finally, the most active compounds have been tested on three cancer cell lines characterized by Src hyperactivation. Compounds 4k and 4l showed an interesting antiproliferative activity on SH-SY5Y neuroblastoma (NB) cell line. In this assay, the compounds resulted more potent than dasatinib, a tyrosine kinase inhibitor approved for the treatment of leukemias and in clinical trials for NB.
2018
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore CHIM/06 - CHIMICA ORGANICA
English
SFK inhibitors; aminoimidazole; anticancer; neuroblastoma; tyrosine kinases; Adenosine Triphosphate; Binding Sites; Cell Line, Tumor; Cell Proliferation; Humans; Imidazoles; Molecular Docking Simulation; Protein Kinase Inhibitors; src-Family Kinases
Francini, C.m., Musumeci, F., Fallacara, A.l., Botta, L., Molinari, A., Artusi, R., et al. (2018). Optimization of aminoimidazole derivatives as Src family kinase inhibitors. MOLECULES, 23(9), 2369 [10.3390/molecules23092369].
Francini, Cm; Musumeci, F; Fallacara, Al; Botta, L; Molinari, A; Artusi, R; Mennuni, L; Angelucci, A; Schenone, S
Articolo su rivista
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/273581
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