Abstract
Using a pyrrole-based scaffold, we developed a series of small molecules that mimic the three-dimensional arrangement of the polar and hydrophobic functional groups of the best cyclic-peptide inhibitor. Iterative optimization cycles of design, synthesis and kinetic testing has lead to an effective inhibitor of Wip1, that is selective for this phosphatase over others. The picture shows the structure of the best inhibitor bound to the active site of the enzyme.
Publication types
-
Research Support, N.I.H., Intramural
MeSH terms
-
Catalytic Domain
-
Drug Design*
-
Enzyme Inhibitors / chemical synthesis
-
Enzyme Inhibitors / pharmacology*
-
Phosphoprotein Phosphatases / antagonists & inhibitors*
-
Phosphorylation
-
Protein Phosphatase 2C
-
Pyrroles / chemical synthesis
-
Pyrroles / pharmacology*
-
Structure-Activity Relationship
-
Substrate Specificity
-
Tumor Suppressor Protein p53 / antagonists & inhibitors*
-
p38 Mitogen-Activated Protein Kinases / metabolism
Substances
-
Enzyme Inhibitors
-
Pyrroles
-
Tumor Suppressor Protein p53
-
p38 Mitogen-Activated Protein Kinases
-
Phosphoprotein Phosphatases
-
Protein Phosphatase 2C