Unveiling the "Three-Finger Pharmacophore" Required for p53-MDM2 Inhibition by Saturation-Transfer Difference (STD) NMR Initial Growth-Rates Approach

Inhibitors of the p53‐MDM2 protein–protein interaction are emerging as a new and validated approach to treating cancer. Herein, we describe the synthesis and inhibitory evaluation of a series of isoquinolin‐1‐one analogues, and highlight the utility of an initial growth‐rates saturation‐transfer difference (STD) NMR approach supported by protein–ligand docking to investigate p53‐MDM2 inhibition. The approach is illustrated by the study of compound 1, providing key insights into the binding mode of this kind of MDM2 ligands and, more importantly, readily unveiling the previously proposed three‐finger pharmacophore requirement for p53‐MDM2 inhibition. Molecular modelling: Inhibitors of the p53‐MDM2 protein–protein interaction are emerging as a new and validated approach to treating cancer. Herein, the synthesis and inhibitory evaluation of a series of isoquinolin‐1‐one analogues is described, and the utility of an initial growth‐rates STD NMR approach supported by protein–ligand docking to investigate p53‐MDM2 inhibition is highlighted (see figure).