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 carboxy...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2014-09, Vol.24 (17), p.4187-4191
Main Authors: Guo, Chuangxing, Hou, Xinjun, Dong, Liming, Marakovits, Joseph, Greasley, Samantha, Dagostino, Eleanor, Ferre, RoseAnn, Catherine Johnson, M., Humphries, Paul S., Li, Haitao, Paderes, Genevieve D., Piraino, Joseph, Kraynov, Eugenia, Murray, Brion W.
Format: Article
Language:English
Subjects:
Anti-cancer
Anti-tumor
Benzimidazoles - chemical synthesis
Benzimidazoles - chemistry
Benzimidazoles - pharmacology
Carboxylic Acids - chemical synthesis
Carboxylic Acids - chemistry
Carboxylic Acids - pharmacology
Catalytic Domain - drug effects
Cell permeability
Dose-Response Relationship, Drug
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Humans
Medicinal chemistry
Mitosis
Molecular Structure
NIMA-Interacting Peptidylprolyl Isomerase
Peptidyl-prolyl isomerase
Peptidylprolyl Isomerase - antagonists & inhibitors
Peptidylprolyl Isomerase - metabolism
Phosphates - chemistry
Phospho-protein epitope
Pin1
PPIase
SBDD
Structural based drug design
Structure-Activity Relationship
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Summary: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.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2014.07.044