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

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

  • J Med Chem. 2017 Oct 12;60(19):8115-8130. doi: 10.1021/acs.jmedchem.7b00912.
Mariateresa Giustiniano 1,  Simona Daniele 2,  Sveva Pelliccia 1,  Valeria La Pietra 1,  Deborah Pietrobono 2,  Diego Brancaccio 1,  Sandro Cosconati 3,  Anna Messere 3,  Stefano Giuntini 4 5,  Linda Cerofolini 4,  Marco Fragai 4 5,  Claudio Luchinat 4 5,  Sabrina Taliani 2,  Giuseppe La Regina 6,  Federico Da Settimo 2,  Romano Silvestri 6,  Claudia Martini 2,  Ettore Novellino 1,  Luciana Marinelli 1
Affiliations

Affiliations

  • 1 Dipartimento di Farmacia, Università degli Studi di Napoli Federico II , Via D. Montesano 49, 80131, Napoli, Italy.
  • 2 Dipartimento di Farmacia, Università di Pisa , 56126 Pisa, Italy.
  • 3 DiSTABiF, Second University of Naples , 81100, Caserta, Italy.
  • 4 Magnetic Resonance Center (CERM), University of Florence , Via L. Sacconi 6, 50019 Sesto Fiorentino (FI), Italy.
  • 5 Department of Chemistry "Ugo Schiff″, University of Florence , Via della Lastruccia 3-13, 50019 Sesto Fiorentino (FI), Italy.
  • 6 Dipartimento di Chimica e Tecnologie del Farmaco, Università La Sapienza , Piazzale Aldo Moro 5, 00185 Roma, Italy.
PMID: 28921985 DOI: 10.1021/acs.jmedchem.7b00912
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.

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