title: Allosteric Wip1 phosphatase inhibition through flap-subdomain interaction.
abstract: Although therapeutic interventions of signal-transduction cascades with targeted kinase inhibitors are a well-established strategy, drug-discovery efforts to identify targeted phosphatase inhibitors have proven challenging. Herein we report a series of allosteric, small-molecule inhibitors of wild-type p53-induced phosphatase (Wip1), an oncogenic phosphatase common to multiple cancers. Compound binding to Wip1 is dependent on a 'flap' subdomain located near the Wip1 catalytic site that renders Wip1 structurally divergent from other members of the protein phosphatase 2C (PP2C) family and that thereby confers selectivity for Wip1 over other phosphatases. Treatment of tumor cells with the inhibitor GSK2830371 increases phosphorylation of Wip1 substrates and causes growth inhibition in both hematopoietic tumor cell lines and Wip1-amplified breast tumor cells harboring wild-type TP53. Oral administration of Wip1 inhibitors in mice results in expected pharmacodynamic effects and causes inhibition of lymphoma xenograft growth. To our knowledge, GSK2830371 is the first orally active, allosteric inhibitor of Wip1 phosphatase.
authors.affiliation: Protein Dynamics Discovery Performance Unit, Cancer Research, Oncology Research and Development, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Aidan G
authors.initials: AG
authors.lastname: Gilmartin
authors.affiliation: Protein Dynamics Discovery Performance Unit, Cancer Research, Oncology Research and Development, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Faitg
authors.affiliation: Protein Dynamics Discovery Performance Unit, Cancer Research, Oncology Research and Development, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Richter
authors.affiliation: Protein Dynamics Discovery Performance Unit, Cancer Research, Oncology Research and Development, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Arthur
authors.initials: A
authors.lastname: Groy
authors.affiliation: Protein Dynamics Discovery Performance Unit, Cancer Research, Oncology Research and Development, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Seefeld
authors.affiliation: Protein Dynamics Discovery Performance Unit, Cancer Research, Oncology Research and Development, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Darcy
authors.affiliation: Protein Dynamics Discovery Performance Unit, Cancer Research, Oncology Research and Development, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Peng
authors.affiliation: Protein Dynamics Discovery Performance Unit, Cancer Research, Oncology Research and Development, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Kelly
authors.initials: K
authors.lastname: Federowicz
authors.affiliation: Protein Dynamics Discovery Performance Unit, Cancer Research, Oncology Research and Development, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Jingsong
authors.initials: J
authors.lastname: Yang
authors.affiliation: Protein Dynamics Discovery Performance Unit, Cancer Research, Oncology Research and Development, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Shu-Yun
authors.initials: SY
authors.lastname: Zhang
authors.affiliation: Protein Dynamics Discovery Performance Unit, Cancer Research, Oncology Research and Development, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Minthorn
authors.affiliation: Platform Technology and Sciences, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Jon-Paul
authors.initials: JP
authors.lastname: Jaworski
authors.affiliation: Platform Technology and Sciences, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Schaber
authors.affiliation: Platform Technology and Sciences, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Stan
authors.initials: S
authors.lastname: Martens
authors.affiliation: Platform Technology and Sciences, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Dean E
authors.initials: DE
authors.lastname: McNulty
authors.affiliation: Platform Technology and Sciences, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Sinnamon
authors.affiliation: Platform Technology and Sciences, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Platform Technology and Sciences, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Kirkpatrick
authors.affiliation: Platform Technology and Sciences, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Neysa
authors.initials: N
authors.lastname: Nevins
authors.affiliation: Platform Technology and Sciences, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Guanglei
authors.initials: G
authors.lastname: Cui
authors.affiliation: Platform Technology and Sciences, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Beth
authors.initials: B
authors.lastname: Pietrak
authors.affiliation: Platform Technology and Sciences, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Elsie
authors.initials: E
authors.lastname: Diaz
authors.affiliation: Platform Technology and Sciences, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Amber
authors.initials: A
authors.lastname: Jones
authors.affiliation: Platform Technology and Sciences, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Brandt
authors.affiliation: Platform Technology and Sciences, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Schwartz
authors.affiliation: Protein Dynamics Discovery Performance Unit, Cancer Research, Oncology Research and Development, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Dirk A
authors.initials: DA
authors.lastname: Heerding
authors.affiliation: Protein Dynamics Discovery Performance Unit, Cancer Research, Oncology Research and Development, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Rakesh
authors.initials: R
authors.lastname: Kumar
mesh_terms: D000284:Administration, Oral; D000494:Allosteric Regulation; D020816:Amino Acid Motifs; D000631:Aminopyridines / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D004151:Dipeptides / Q000737:chemistry* / Q000494:pharmacology; D004195:Disease Models, Animal; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D064593:Heterografts; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D008954:Models, Biological; D009369:Neoplasms; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors*; D000071636:Protein Phosphatase 2C
chemical_list: D000631:Aminopyridines; D000970:Antineoplastic Agents; D004151:Dipeptides; D004791:Enzyme Inhibitors; C587624:GSK2830371; C000607456:PPM1A protein, human; C000607457:PPM1B protein, human; C000607458:PPM1D protein, human; C000607460:PPM1G protein, human; D010749:Phosphoprotein Phosphatases; C000607468:Ppm1d protein, mouse; D000071636:Protein Phosphatase 2C