title: Synthesis and properties of a selective inhibitor of homeodomain-interacting protein kinase 2 (HIPK2).
abstract: Homeodomain-interacting protein kinase 2 (HIPK2) is a Ser/Thr kinase controlling cell proliferation and survival, whose investigation has been hampered by the lack of specific inhibitors able to dissect its cellular functions. SB203580, a p38 MAP kinase inhibitor, has been used as a tool to inhibit HIPK2 in cells, but here we show that its efficacy as HIPK2 inhibitor is negligible (IC₅₀>40 µM). In contrast by altering the scaffold of the promiscuous CK2 inhibitor TBI a new class of HIPK2 inhibitors has been generated. One of these, TBID, displays toward HIPK2 unprecedented efficacy (IC₅₀ = 0.33 µM) and selectivity (Gini coefficient 0.592 out of a panel of 76 kinases). The two other members of the HIPK family, HIPK1 and HIPK3, are also inhibited by TBID albeit less efficiently than HIPK2. The mode of action of TBID is competitive with respect to ATP, consistent with modelling. We also provide evidence that TBID is cell permeable by showing that HIPK2 activity is reduced in cells treated with TBID, although with an IC₅₀ two orders of magnitude higher (about 50 µM) than in vitro.
authors.affiliation: Department of Biomedical Sciences, University of Padova, and CNR Institute of Neurosciences, Padova, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Cozza
authors.affiliation: Department of Biomedical Sciences, University of Padova, and CNR Institute of Neurosciences, Padova, Italy.
authors.forename: Sofia
authors.initials: S
authors.lastname: Zanin
authors.affiliation: Technische Universität Braunschweig, Institut für Medizinische und Pharmazeutische Chemie, Braunschweig, Germany.
authors.forename: Renate
authors.initials: R
authors.lastname: Determann
authors.affiliation: Department of Biomedical Sciences, University of Padova, and CNR Institute of Neurosciences, Padova, Italy ; Venetian Institute of Molecular Medicine (VIMM), Padova, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Ruzzene
authors.affiliation: Technische Universität Braunschweig, Institut für Medizinische und Pharmazeutische Chemie, Braunschweig, Germany.
authors.forename: Conrad
authors.initials: C
authors.lastname: Kunick
authors.affiliation: Department of Biomedical Sciences, University of Padova, and CNR Institute of Neurosciences, Padova, Italy ; Venetian Institute of Molecular Medicine (VIMM), Padova, Italy.
authors.forename: Lorenzo A
authors.initials: LA
authors.lastname: Pinna
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D002352:Carrier Proteins; D047428:Protein Kinase Inhibitors; D000255:Adenosine Triphosphate; C115114:HIPK2 protein, human; D017346:Protein Serine-Threonine Kinases