title: Novel inhibitors targeting PPM1D phosphatase potently suppress cancer cell proliferation.
abstract: Protein phosphatase magnesium-dependent 1δ (PPM1D, Wip1) is a p53 inducible serine/threonine phosphatase. PPM1D is a promising target protein in cancer therapy since overexpression, missense mutations, truncating mutations, and gene amplification of PPM1D are reported in many tumors, including breast cancer and neuroblastoma. Herein, we report that a specific inhibitor, SL-176 that can be readily synthesized in 10 steps, significantly inhibits proliferation of a breast cancer cell line overexpressing PPM1D and induces G2/M arrest and apoptosis. SL-176 decreases PPM1D enzyme activity potently and specifically in vitro. These results demonstrate that SL-176 could be a useful lead compound in the development of effective anti-cancer agents.
authors.affiliation: Laboratory of Biological Chemistry, Department of Chemistry, Faculty of Science, Hokkaido University, North 10, West 8, Kita-ku, Sapporo 060-0810, Japan.
authors.forename: Sari
authors.initials: S
authors.lastname: Ogasawara
authors.affiliation: Laboratory of Biological Chemistry, Department of Chemistry, Faculty of Science, Hokkaido University, North 10, West 8, Kita-ku, Sapporo 060-0810, Japan.
authors.forename: Yuhei
authors.initials: Y
authors.lastname: Kiyota
authors.affiliation: Laboratory of Biological Chemistry, Department of Chemistry, Faculty of Science, Hokkaido University, North 10, West 8, Kita-ku, Sapporo 060-0810, Japan.
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Chuman
authors.affiliation: Laboratory of Organic Chemistry II, Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo 060-0810, Japan.
authors.forename: Ayano
authors.initials: A
authors.lastname: Kowata
authors.affiliation: Laboratory of Organic Chemistry II, Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo 060-0810, Japan.
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Yoshimura
authors.affiliation: Laboratory of Organic Chemistry II, Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo 060-0810, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Tanino
authors.affiliation: Laboratory of Biological Chemistry, Department of Chemistry, Faculty of Science, Hokkaido University, North 10, West 8, Kita-ku, Sapporo 060-0810, Japan.
authors.forename: Rui
authors.initials: R
authors.lastname: Kamada
authors.affiliation: Laboratory of Biological Chemistry, Department of Chemistry, Faculty of Science, Hokkaido University, North 10, West 8, Kita-ku, Sapporo 060-0810, Japan. Electronic address: kazuyasu@sci.hokudai.ac.jp.
authors.forename: Kazuyasu
authors.initials: K
authors.lastname: Sakaguchi
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071636:Protein Phosphatase 2C; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D016159:Tumor Suppressor Protein p53; C000607458:PPM1D protein, human; D010749:Phosphoprotein Phosphatases; D000071636:Protein Phosphatase 2C
keywords: Anti-tumor; Apoptosis; Dephosphorylation; Inhibitors; Protein phosphatase