Computer-Aided Identification and Lead Optimization of Dual Murine Double Minute 2 and 4 Binders: Structure–Activity Relationship Studies and Pharmacological Activity
datasetposted on 2017-09-18, 00:00 authored by Mariateresa Giustiniano, Simona Daniele, Sveva Pelliccia, Valeria La Pietra, Deborah Pietrobono, Diego Brancaccio, Sandro Cosconati, Anna Messere, Stefano Giuntini, Linda Cerofolini, Marco Fragai, Claudio Luchinat, Sabrina Taliani, Giuseppe La Regina, Federico Da Settimo, Romano Silvestri, Claudia Martini, Ettore Novellino, Luciana Marinelli
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.
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NMR studies4.6 nMminute 2 proteinLead Optimizationhouse databaseblock cancerPharmacological ActivityCompound 14 Binderscell proliferationMDM 2.Glide docking softwareIC 50 valuecell growthIC 50neuroblastoma SHSY 5Y cellsComputer-Aided Identificationcompound 12MDM 2-selective inhibitorsMDM 2p 53 proteinnanomolar IC 50Dual Murine Double Minute 2cause concentration-dependent inhibition