Computer-Aided Identification and Lead Optimization of Dual Murine Double Minute 2 and 4 Binders: Structure-Activity Relationship Studies and Pharmacological Activity.
Mariateresa GiustinianoSimona DanieleSveva PellicciaValeria La PietraDeborah PietrobonoDiego BrancaccioSandro CosconatiAnna MessereStefano GiuntiniLinda CerofoliniMarco FragaiClaudio LuchinatSabrina TalianiGiuseppe La ReginaFederico Da SettimoRomano SilvestriClaudia MartiniEttore NovellinoLuciana MarinelliPublished in: Journal of medicinal chemistry (2017)
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.
Keyphrases
- cell proliferation
- protein protein
- magnetic resonance
- photodynamic therapy
- squamous cell carcinoma
- gene expression
- high resolution
- molecular dynamics
- induced apoptosis
- structure activity relationship
- emergency department
- cell death
- cell cycle
- mass spectrometry
- endoplasmic reticulum stress
- oxidative stress
- dna binding
- lymph node metastasis