Structure-based design of novel human Pin1 inhibitors (III): optimizing affinity beyond the phosphate recognition pocket

The design of potent PIN1 inhibitors has been challenging because its active site specifically recognizes a phospho-protein epitope. The de novo design of phosphate-based PIN1 inhibitors focusing on the phosphate recognition pocket and the successful replacement of the phosphate group with a carboxylate have been previously reported. The potency of the carboxylate series is now further improved through structure-based optimization of ligand-protein interactions in the proline binding site which exploits the H-bond interactions necessary for PIN1 catalytic function. Further optimization using a focused library approach led to the discovery of low nanomolar non-phosphate small molecular PIN1 inhibitors. Structural modifications designed to improve cell permeability resulted in PIN1 inhibitors with low micromolar anti-proliferative activities against Cancer cells.