Molecules, Vol. 23, Pages 2369: Optimization of Aminoimidazole Derivatives as Src Family Kinase Inhibitors

Molecules, Vol. 23, Pages 2369: Optimization of Aminoimidazole Derivatives as Src Family Kinase Inhibitors Molecules doi: 10.3390/molecules23092369 Authors: Cinzia Maria Francini Francesca Musumeci Anna Lucia Fallacara Lorenzo Botta Alessio Molinari Roberto Artusi Laura Mennuni Adriano Angelucci Silvia Schenone 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 IC50s 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) ce...
Source: Molecules - Category: Chemistry Authors: Tags: Article Source Type: research