title: Synthesis and biological evaluation of 3-aminoisoquinolin-1(2H)-one based inhibitors of the dual-specificity phosphatase Cdc25B.
abstract: The cell division cycle 25B dual specificity phosphatase (Cdc25B) regulates the normal progression of the mammalian cell cycle by dephosphorylating and activating cyclin-dependent kinase (Cdk) complexes, particularly in response to DNA damage. Elevated Cdc25B levels enable a bypass of normal cell cycle checkpoints, and the overexpression of Cdc25B has been linked to a variety of human cancers. Thus, Cdc25B is an attractive target for the development of anticancer therapeutics. Herein we describe the synthesis and biological evaluation of a series of non-quinoid inhibitors of Cdc25B containing the 3-aminoisoquinolin-1(2H)-one pharmacophore. In addition to several strategies that address specific substitution patterns on isoquinolines, we have applied a regioselective Pd-catalyzed cross-coupling methodology to synthesize a new lead structure, 6-(3-aminophenyl)-3-(phenylamino)isoquinolin-1(2H)-one (13), which proved to be a reversible, competitive Cdc25B inhibitor with a Ki of 1.9μM. Compound 13 prevented human cancer cell growth and blocked Cdc25B-mediated mitotic checkpoint bypass. Molecular docking studies support binding near the catalytic site.
authors.affiliation: Department of Chemistry, University of Pittsburgh, 219 Parkman Avenue, Pittsburgh, PA 15260, USA.
authors.forename: Kara M
authors.initials: KM
authors.lastname: George Rosenker
authors.affiliation: Department of Chemistry, University of Pittsburgh, 219 Parkman Avenue, Pittsburgh, PA 15260, USA.
authors.forename: William D
authors.initials: WD
authors.lastname: Paquette
authors.affiliation: Department of Pharmaceutical Sciences, University of Pittsburgh, 3501 5th Avenue, Pittsburgh, PA 15260, USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Johnston
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Sharlow
authors.affiliation: Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA 15260, USA.
authors.forename: Andreas
authors.initials: A
authors.lastname: Vogt
authors.affiliation: Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA 15260, USA.
authors.forename: Ahmet
authors.initials: A
authors.lastname: Bakan
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA. Electronic address: lazo@virginia.edu.
authors.forename: John S
authors.initials: JS
authors.lastname: Lazo
authors.affiliation: Department of Chemistry, University of Pittsburgh, 219 Parkman Avenue, Pittsburgh, PA 15260, USA; Department of Pharmaceutical Sciences, University of Pittsburgh, 3501 5th Avenue, Pittsburgh, PA 15260, USA; Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15260, USA. Electronic address: pwipf@pitt.edu.
authors.forename: Peter
authors.initials: P
authors.lastname: Wipf
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology; D020687:cdc25 Phosphatases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007546:Isoquinolines; C517008:CDC25B protein, human; D020687:cdc25 Phosphatases; C041545:1-aminoisoquinoline
keywords: 3-Amino-1,2-dihydro-1-isoquinolinone; Cdc25B; Checkpoint bypass; Molecular docking; Palladium cross-coupling