title: Small-molecule inhibition of PTPRZ reduces tumor growth in a rat model of glioblastoma.
abstract: Protein tyrosine phosphatase receptor-type Z (PTPRZ) is aberrantly over-expressed in glioblastoma and a causative factor for its malignancy. However, small molecules that selectively inhibit the catalytic activity of PTPRZ have not been discovered. We herein performed an in vitro screening of a chemical library, and identified SCB4380 as the first potent inhibitor for PTPRZ. The stoichiometric binding of SCB4380 to the catalytic pocket was demonstrated by biochemical and mass spectrometric analyses. We determined the crystal structure of the catalytic domain of PTPRZ, and the structural basis of the binding of SCB4380 elucidated by a molecular docking method was validated by site-directed mutagenesis studies. The intracellular delivery of SCB4380 by liposome carriers inhibited PTPRZ activity in C6 glioblastoma cells, and thereby suppressed their migration and proliferation in vitro and tumor growth in a rat allograft model. Therefore, selective inhibition of PTPRZ represents a promising approach for glioma therapy.
authors: Division of Molecular Neurobiology, National Institute for Basic Biology (NIBB), 5-1 Higashiyama, Myodaiji-cho, Okazaki, Aichi, 444-8787, Japan.
authors: Akihiro
authors: A
authors: Fujikawa
authors: Asubio Pharma Co., Ltd., 6-4-3 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan.
authors: Asako
authors: A
authors: Nagahira
authors: Asubio Pharma Co., Ltd., 6-4-3 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan.
authors: Hajime
authors: H
authors: Sugawara
authors: Department of Bioorganization Research, Okazaki Institute for Integrative Bioscience, 5-1 Higashiyama, Myodaiji-cho, Okazaki, Aichi, 444-8787, Japan.
authors: Kentaro
authors: K
authors: Ishii
authors: Asubio Pharma Co., Ltd., 6-4-3 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan.
authors: Seiichi
authors: S
authors: Imajo
authors: Division of Molecular Neurobiology, National Institute for Basic Biology (NIBB), 5-1 Higashiyama, Myodaiji-cho, Okazaki, Aichi, 444-8787, Japan.
authors: Masahito
authors: M
authors: Matsumoto
authors: Division of Molecular Neurobiology, National Institute for Basic Biology (NIBB), 5-1 Higashiyama, Myodaiji-cho, Okazaki, Aichi, 444-8787, Japan.
authors: Kazuya
authors: K
authors: Kuboyama
authors: Division of Molecular Neurobiology, National Institute for Basic Biology (NIBB), 5-1 Higashiyama, Myodaiji-cho, Okazaki, Aichi, 444-8787, Japan.
authors: Ryoko
authors: R
authors: Suzuki
authors: Division of Molecular Neurobiology, National Institute for Basic Biology (NIBB), 5-1 Higashiyama, Myodaiji-cho, Okazaki, Aichi, 444-8787, Japan.|School of Life Science, The Graduate University for Advanced Studies (SOKENDAI), 5-1 Higashiyama, Myodaiji-cho, Okazaki, Aichi, 444-8787, Japan.
authors: Naomi
authors: N
authors: Tanga
authors: Department of Biotechnology, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors: Masanori
authors: M
authors: Noda
authors: Department of Bioorganization Research, Okazaki Institute for Integrative Bioscience, 5-1 Higashiyama, Myodaiji-cho, Okazaki, Aichi, 444-8787, Japan.|Department of Biotechnology, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors: Susumu
authors: S
authors: Uchiyama
authors: Asubio Pharma Co., Ltd., 6-4-3 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan.
authors: Toshiyuki
authors: T
authors: Tomoo
authors: Asubio Pharma Co., Ltd., 6-4-3 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan.
authors: Atsuto
authors: A
authors: Ogata
authors: Asubio Pharma Co., Ltd., 6-4-3 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan.
authors: Makoto
authors: M
authors: Masumura
authors: Division of Molecular Neurobiology, National Institute for Basic Biology (NIBB), 5-1 Higashiyama, Myodaiji-cho, Okazaki, Aichi, 444-8787, Japan.|School of Life Science, The Graduate University for Advanced Studies (SOKENDAI), 5-1 Higashiyama, Myodaiji-cho, Okazaki, Aichi, 444-8787, Japan.
authors: Masaharu
authors: M
authors: Noda
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D005909:Glioblastoma / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D008297:Male; D062105:Molecular Docking Simulation; D016297:Mutagenesis, Site-Directed; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D009363:Neoplasm Proteins; C516897:Ptprz1 protein, rat; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5