Computer-Aided Identification and Lead Optimization of Dual Murine Double Minute 2 and 4 Binders: Structure–Activity Relationship Studies and Pharmacological Activity

5 years ago

Computer-Aided Identification and Lead Optimization of Dual Murine Double Minute 2 and 4 Binders: Structure–Activity Relationship Studies and Pharmacological Activity

Stefano Giuntini, Deborah Pietrobono, Sveva Pelliccia, Mariateresa Giustiniano, Claudia Martini, Luciana Marinelli, Linda Cerofolini, Anna Messere, Diego Brancaccio, Simona Daniele, Romano Silvestri, Sabrina Taliani, Sandro Cosconati, Valeria La Pietra, Claudio Luchinat, Ettore Novellino, Federico Da Settimo, Giuseppe La Regina, Marco Fragai

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.

Publisher URL: http://dx.doi.org/10.1021/acs.jmedchem.7b00912

DOI: 10.1021/acs.jmedchem.7b00912