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Structure-based design of novel human Pin1 inhibitors (III): Optimizing affinity beyond the phosphate recognition pocket |
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| Affiliation: | 1. Fujian Key Laboratory for Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian 350108, China;2. Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian 350108, China;3. Division of Translational Therapeutics, Department of Medicine and Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA;4. Institute of Biomaterials and Tissue Engineering, Huaqiao University, Xiamen, Fujian 361021, China;5. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA |
| Abstract: | 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. |
| Keywords: | Pin1 Peptidyl-prolyl isomerase PPIase Phospho-protein epitope Anti-cancer Anti-tumor Mitosis SBDD Structural based drug design Medicinal chemistry Cell permeability |
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