title: Inhibition of CDC25B phosphatase through disruption of protein-protein interaction.
abstract: CDC25 phosphatases are key cell cycle regulators and represent very attractive but challenging targets for anticancer drug discovery. Here, we explored whether fragment-based screening represents a valid approach to identify inhibitors of CDC25B. This resulted in identification of 2-fluoro-4-hydroxybenzonitrile, which directly binds to the catalytic domain of CDC25B. Interestingly, NMR data and the crystal structure demonstrate that this compound binds to the pocket distant from the active site and adjacent to the protein-protein interaction interface with CDK2/Cyclin A substrate. Furthermore, we developed a more potent analogue that disrupts CDC25B interaction with CDK2/Cyclin A and inhibits dephosphorylation of CDK2. Based on these studies, we provide a proof of concept that targeting CDC25 phosphatases by inhibiting their protein-protein interactions with CDK2/Cyclin A substrate represents a novel, viable opportunity to target this important class of enzymes.
authors.affiliation: Department of Pathology, University of Michigan , 4510C MSRBI 1150 West Medical Center Drive, Ann Arbor, Michigan 48109-5620, United States.
authors.forename: George
authors.initials: G
authors.lastname: Lund
authors.forename: Sergii
authors.initials: S
authors.lastname: Dudkin
authors.forename: Dmitry
authors.initials: D
authors.lastname: Borkin
authors.forename: Wendi
authors.initials: W
authors.lastname: Ni
authors.forename: Jolanta
authors.initials: J
authors.lastname: Grembecka
authors.forename: Tomasz
authors.initials: T
authors.lastname: Cierpicki
mesh_terms: D001665:Binding Sites; D003460:Crystallization; D019925:Cyclin A / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D004791:Enzyme Inhibitors; D004926:Escherichia coli; D015964:Gene Expression Regulation, Bacterial / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D011485:Protein Binding; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D054852:Small Molecule Libraries; D020687:cdc25 Phosphatases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: D019925:Cyclin A; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D054852:Small Molecule Libraries; D051357:Cyclin-Dependent Kinase 2; D020687:cdc25 Phosphatases