The function of p53 protein, also known as “genome guardian”, might be impaired by the overexpression of its primary cellular inhibitor, the murine double minute 2 protein (MDM2). However, the recent finding that MDM2-selective inhibitors induce high levels of its homologue MDM4, prompt us to identify, through a receptor-based virtual screening on an in house database, dual MDM2/MDM4 binders. Compound 1 turned out to possess an IC50 of 93.7 and of 4.6 nM on MDM2 and MDM4, respectively. A series of compounds were synthesized to optimize its activity on MDM2. As a result, compound 12 showed low nanomolar IC50 for both targets. NMR studies confirmed the pocket of binding of 12 as predicted by the Glide docking software. Notably, 12 was able to cause concentration-dependent inhibition of cell proliferation, yielding an IC50 value of 356 ± 21 nM in neuroblastoma SHSY5Y cells and proved even to efficiently block cancer stem cell growth.

Computer-aided identification and lead optimization of dual murine double minute 2 and 4 binders: structure-activity relationship studies and pharmacological activity / Giustiniano, M.; Daniele, S.; Pelliccia, S.; La Pietra, V.; Pietrobono, D.; Brancaccio, D.; Cosconati, S.; Messere, A.; Giuntini, S.; Cerofolini, L.; Fragai, M.; Luchinat, C.; Taliani, S.; La Regina, G.; Da Settimo, F.; Silvestri, R.; Martini, C.; Novellino, E.; Marinelli, L.. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - STAMPA. - 60:19(2017), pp. 8115-8130. [10.1021/acs.jmedchem.7b00912]

Computer-aided identification and lead optimization of dual murine double minute 2 and 4 binders: structure-activity relationship studies and pharmacological activity

Pelliccia, S.;La Regina, G.;Silvestri, R.;
2017

Abstract

The function of p53 protein, also known as “genome guardian”, might be impaired by the overexpression of its primary cellular inhibitor, the murine double minute 2 protein (MDM2). However, the recent finding that MDM2-selective inhibitors induce high levels of its homologue MDM4, prompt us to identify, through a receptor-based virtual screening on an in house database, dual MDM2/MDM4 binders. Compound 1 turned out to possess an IC50 of 93.7 and of 4.6 nM on MDM2 and MDM4, respectively. A series of compounds were synthesized to optimize its activity on MDM2. As a result, compound 12 showed low nanomolar IC50 for both targets. NMR studies confirmed the pocket of binding of 12 as predicted by the Glide docking software. Notably, 12 was able to cause concentration-dependent inhibition of cell proliferation, yielding an IC50 value of 356 ± 21 nM in neuroblastoma SHSY5Y cells and proved even to efficiently block cancer stem cell growth.
2017
p53 protein; MDM2/MDM4 binders; neuroblastoma cells
01 Pubblicazione su rivista::01a Articolo in rivista
Computer-aided identification and lead optimization of dual murine double minute 2 and 4 binders: structure-activity relationship studies and pharmacological activity / Giustiniano, M.; Daniele, S.; Pelliccia, S.; La Pietra, V.; Pietrobono, D.; Brancaccio, D.; Cosconati, S.; Messere, A.; Giuntini, S.; Cerofolini, L.; Fragai, M.; Luchinat, C.; Taliani, S.; La Regina, G.; Da Settimo, F.; Silvestri, R.; Martini, C.; Novellino, E.; Marinelli, L.. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - STAMPA. - 60:19(2017), pp. 8115-8130. [10.1021/acs.jmedchem.7b00912]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1026343
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