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

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.