Development and Application of"Cancer Cell lnformatics" for identifying novel drug seeds

2008 Fiscal Year Final Research Report

• Project/Area Number: 17390032
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Drug development chemistry
• Research Institution: Japanese Foundation For Cancer Research
• Principal Investigator: YAMORI Takao Japanese Foundation For Cancer Research, 分子薬理部, 部長 (60200854)
• Co-Investigator(Kenkyū-buntansha): DAN Shingo 財団法人癌研究会・癌化学療法センター, 分子薬理部, 研究員 (70332202)
• Project Period (FY): 2005 – 2008
• Keywords: Cancer Ce11 Informatics / 分子標的予測 / がん / がん細胞パネル / PI3K / 薬剤感受性 / 抗がん剤探索 / データベース

Research Abstract

抗がん剤として分子標的薬の創薬が注目されている。われわれは、生物学的実験とコンピュータを組み合わせることによって化合物の分子標的を予測するユニークなシステムを開発し、これを実際に創薬に応用した。多くの新規化合物を試験した結果、PI3キナーゼ(がんの悪性増殖の原因、がん治療の有力な分子標的の一つ)を標的として攻撃する新規化合物ZSTK474をはじめとする種々の分子標的薬候補を見出すことができた。よって、本システムは分子標的薬の開発を支援、加速するものと考えられ、今後の活用が期待できる。

Research Products

• [Journal Article] SKl and MELl cooperate to inhibit transforming growth factor-beta signal in gastric cancer cells (2009)
  • Author(s): Takahata M, lnoue Y, Tsuda H, lmoto l, Koinuma D, Hayashi M, lchikura T, Yamori T, Nagasaki K, Yoshida M, Matsuoka M, Morishita K, Yuki K, Hanyu A, Miyazawa K, lnazawa J, Miyazono K, Tmamura T
  • Journal Title: The Journal of biological chemistry 284(5) Pages: 3334-44
• [Journal Article] Effect of ZSTK474, a Novel Phosphatidylinositol 3-Kinase lnhibitor, on DNA-Dependent Protein Kinase (2009)
  • Author(s): Kong D, Yaguchi S, Yamori T
  • Journal Title: Biological&pharmaceutical bulletin 32(2) Pages: 297-300
• [Journal Article] Antiangiogenic effect of ZSTK474, a novel phosphatidylinositol 3-kinase inhibitor (2009)
  • Author(s): Kong D, 0kamura M, Yoshimi H, Yamori T
  • Journal Title: Eur J Cancer 45(5) Pages: 857-65
• [Journal Article] Inhibition of PI3K by ZSTK474 suppressed tumor growth not via apoptosis but GO/Gl arrest (2009)
  • Author(s): Dan S, Yoshimi H, 0kamura M, Mukai Y, Yamori T
  • Journal Title: Biochemical and biophysical research communications 379(1) Pages: 104-9
• [Journal Article] Proteomic analysis of phosphoproteins sensitive to a phosphatidylinositol 3-kinase inhibitor, ZSTK474, by using SELDI-TOF MS (2009)
  • Author(s): Akashi T, Yamori T
  • Journal Title: Proteome science 7 Pages: 14
• [Journal Article] A new evaluation method for quantifying PI3K activity by HTRF assay (2008)
  • Author(s): Sugita H, Dan S, Kong D, Tomida A, Yamori T
  • Journal Title: Biochemical and biophysical research communications 377(3) Pages: 941-5
• [Journal Article] Synthesis and pharmacological evaluation of the novel pseudo-symmetrical tamoxifen derivatives as anti-tumor agents (2008)
  • Author(s): Shiina I, Sano Y, Nakata K, Kikuchi T, Sasaki A, Ikekita M, Nagahara Y,Hasome Y, Yamori T, Yamazaki K
  • Journal Title: Biochem Pharmacol 75(5) Pages: 1014-26
• [Journal Article] Phosphatidylinositol 3-kinase inhibitors : promising drug candidates for cancer therapy (2008)
  • Author(s): Kong D, Yamori T
  • Journal Title: Cancer science 99(9) Pages: 1734-40
• [Journal Article] Synthesis of C4-fluorinated solamins and their growth inhibitory activity against human cancer cell lines (2008)
  • Author(s): Kojima N, Hayashi H, Suzuki S, Tominaga H, Maezaki N, Tanaka T, Yamori T
  • Journal Title: Bioorganic & medicinal chemistry letters 18(24) Pages: 6451-3
• [Journal Article] Synthesis of hybrid acetogenins, alpha, beta-unsaturated-gamm a-lactone-free nitrogen-containing heterocyclic analogues, and their cytotoxicity against human cancer cell lines (2008)
  • Author(s): Kojima N, Fushimi T, Maezaki N, Tanaka T, Yamori T
  • Journal Title: Bioorganic & medicinal chemistry letters 18(5) Pages: 1637-41
• [Journal Article] Anticancer mechanisms of YC-1 in human lung cancer cell line, NCI-H226 (2008)
  • Author(s): Chen CJ, Hsu MH, Huang LJ, Yamori T, Chung JG, Lee FY, Teng CM, Kuo SC
  • Journal Title: Biochem Pharmacol 75(2) Pages: 360-8
• [Journal Article] Glaziovianin A,a new isoflavone, from the leaves of Ateleia glazioviana and its cytotoxic activity against human cancer cells (2007)
  • Author(s): Yokosuka A, Haraguchi M, Usui T, Kazami S, 0sada H, Yamori T, Mimaki Y
  • Journal Title: Bioorganic & medicinal chemistry letters 17(11) Pages: 3091-4
• [Journal Article] Identification of JTP-70902, a p15(INK4♭)-inductive compound, as a novel MEK1/2 inhibitor (2007)
  • Author(s): Yamaguchi T, Yoshida T, Kurachi R, Kakegawa J, Hori Y, Nanayama T, Hayakawa K, Abe H, Takagi K, Matsuzaki Y, Koyama M, Yogosawa S, Sowa Y, Yamori T, Tajima N, Sakai T
  • Journal Title: Cancer science 98(11) Pages: 1809-16
• [Journal Article] Evaluation of Action Mechanisms of Toxic Chemicals using JFCR39, a Panel of Human Cancer Cell lines (2007)
  • Author(s): Nakatsu N, Nakamura T, Yamazaki K, Sadahiro S, Makuuchi H, Kanno J, Yamori T
  • Journal Title: Mol Pharmacol 72(5) Pages: 1171-80
• [Journal Article] Absolute quantification of four isoforms of the class I phosphoinositide-3-kinase catalytic subunit by real-time RT-PCR (2007)
  • Author(s): Nakamura H, Dan S, Akashi T,Unno M, Yamori T
  • Journal Title: Biological & pharmaceutical bulletin 30(6) Pages: 1181-4
• [Journal Article] Sesquiterpenoids and flavonoids from the aerial parts of Tithonia diversifolia and their cytotoxic activity (2007)
  • Author(s): Kuroda M, Yokosuka A, Kobayashi R, Jitsuno M, Kando H, Nosaka K, Ishii H, Yamori T, Mimaki Y
  • Journal Title: Chemical & pharmaceutical bulletin 55(8) Pages: 1240-4
• [Journal Article] ZSTK474 is an ATP-competitive inhibitor of class I phosphatidylinositol 3kinase isoforms (2007)
  • Author(s): Kong D ,Yamori T
  • Journal Title: Cancer science 98(10) Pages: 1638-42
• [Journal Article] Marine diterpenoids with a briarane skeleton from the okinawan soft cora1 Pachyclavularia violacea (2007)
  • Author(s): Ito H, lwasaki J, Sato Y, Aoyagi M, Iguchi K, Yamori T
  • Journal Title: Chemical & pharmaceutical bulletin 55(12) Pages: 1671-6
• [Journal Article] Development and characterization of a model of liver metastasis using human colon cancer HCT-II6 cells (2007)
  • Author(s): Ishizu K, Sunose N, Yamazaki K, Tsuruo T, Sadahiro S, Makuuchi H, Yamori T
  • Journal Title: Biological & pharmaceutical bulletin 30(9) Pages: 1779-83
• [Journal Article] Enantioselective Total Synthesis of (+)-Ottelione A, (-)-Ottelione B, (+)-3-epi-Ottelione A and Preliminary Evaluation of Their Antitumor Activity (2007)
  • Author(s): Araki H, Inoue M, Suzuki T, Yamori T,Kohno M, Watanabe K, Abe H, Katoh T
  • Journal Title: Chemistry 13(35) Pages: 9866-81
• [Journal Article] Variation in cytostatic constituents of asponge-derived Gymnascella dankaliensis by manipulating the carbon source (2007)
  • Author(s): Amagata T, Tanaka M, Yamada T, Doi M, Minoura K, 0hishi H, Yamori T, Numata A
  • Journal Title: Journal of natural products 70(11) Pages: 1731-40
• [Journal Article] A novel method for analyzing phosphoproteins using SELDI-TOF MS in combination with a series of recombinant proteins (2007)
  • Author(s): Akashi T, Yamori T
  • Journal Title: Proteomics 7(14) Pages: 2350-4
• [Journal Article] Proteomics-based identification of biomarkers for predicting sensitivity to a PI3-kinase inhibitor in cancer (2007)
  • Author(s): Akashi T, Nishimura Y, Wakatabe R, Shiwa M, Yamori T
  • Journal Title: Biochemicaland biophysical research communications 352(2) Pages: 514-21
• [Journal Article] Antitumor activity of ZSTK474,a new phosphatidylinositol 3-kinase inhibitor (2006)
  • Author(s): Yaguchi S, Fukui Y, Koshimizu I, Yoshimi H, Matsuno T, Gouda H, Hirono S, Yamazaki K, Yamori T
  • Journal Title: J Nat1 Cancer Inst 98(8) Pages: 545-56
• [Journal Article] Potent antitumor activity of 3,4-seco-8betaH-Ferna-4(23), 9(11)-die n-3-oic acid (EC-2) and 3,4-seco-01eana-4(23), 18-dien-3-oic acid(EC-4), evaluated by an in vitro human cancer cell line panel (2006)
  • Author(s): Tanaka R, Wada S, Yamada T, Yamori T
  • Journal Title: Planta Med 72(14) Pages: 1347-9
• [Journal Article] Synthesis and biological evaluation of boronic acid containing cis-stilbenes as apoptotic tubulin polymerization inhibitors (2006)
  • Author(s): Nakamura H, Kuroda H, Saito H, Suzuki R, Yamori T, Maruyama K, Haga T
  • Journal Title: ChemMedChem 1(7) Pages: 729-40
• [Journal Article] Autotaxin is overexpressed in glioblastoma multiforme and contributes to cell motility of glioblastoma by converting lysophosphatidylcholine to lysophosphatidic acid (2006)
  • Author(s): Kishi Y, 0kudaira S, Tanaka M, Hama K, Shida D, Kitayama J, Yamori T, Aoki J, Fujimaki T, Arai H
  • Journal Title: he Journal of biological chemistry 281(25) Pages: 17492-500
• [Journal Article] Modification of pyrimidine derivatives from antiviral agents to antitumor agents (2006)
  • Author(s): Kimura H, Katoh T, Kajimoto T, Node M, Hisaki M, Sugimoto Y, Majima T, Uehara Y, Yamori T
  • Journal Title: Anticancer Res 26(1A) Pages: 91-7
• [Journal Article] Leptosins isolated from marine fungus Leptoshaeria species inhibit DNA topoisomerases I and/or II and induce apoptosis by inactivation of Akt/protein kinase B (2005)
  • Author(s): Yanagihara M, Sasaki-Takahashi N, Sugahara T, Yamamoto S, Shinomi M, Yamashita I, Hayashida M, Yamanoha B, Numata A,Yamori T, Andoh T
  • Journal Title: Cancer science 96(11) Pages: 816-24
• [Journal Article] YM-216391, a novel cytotoxic cyclic peptide from Streptomyces nobilis. I.fermentation, isolation and biological activities (2005)
  • Author(s): Sohda KY, Nagai K, Yamori T, Suzuki K, Tanaka A
  • Journal Title: The Journal of antibiotics 58(I) Pages: 27-31
• [Journal Article] Selective sensitivity to wasabi-derived 6-(methylsulfinyl)hexy lisothiocyanate of human breast cancer and melanoma cell lines studied in vitro (2005)
  • Author(s): Nomura T, Shinoda S, Yamori T, Sawaki S, Nagata I, Ryoyama K, Fuke Y
  • Journal Title: Cancer Detect Prev 29(2) Pages: 155-60
• [Journal Article] Chemosensitivity profile of cancer cell lines and identification of genes determining chemosensitivity by an integrated bioinformatical approach using cDNA arrays (2005)
  • Author(s): Nakatsu N, Yoshida Y, Yamazaki K, Nakamura T, Dan S, Fukui Y, Yamori T
  • Journal Title: Mol Cancer Ther 4(3) Pages: 399-412
• [Journal Article] p53-defective tumors with a functional apoptosome-mediated pathway : a new therapeutic target (2005)
  • Author(s): Mashima T, 0h-hara T, Sato S,Mochizuki M, Sugimoto Y, Yamazaki K, Hamada J, Tada M, Moriuchi T, Ishikawa Y, Kato Y, Tomoda H, Yamori T, Tsuruo T
  • Journal Title: J Nat1 Cancer Inst 97(10) Pages: 765-77
• [Journal Article] Total Synthesis of Murisolins and Evaluation of Tumor-Growth Inhibitory Activity (2005)
  • Author(s): Maezaki N, Tominaga H, Kojima N, Yanai M, Urabe D, Ueki R, Tanaka T, Yamori T
  • Journal Title: Chemistry 11(21) Pages: 6237-45
• [Journal Article] Synthesis and biological elationships of 3', 6-substituted 2-phenyl-4-quinolone-3-carboxylic acid derivatives as antimitotic agents (2005)
  • Author(s): Lai YY,Huang LJ,Lee KH,xiao Z, Bastow KF, Yamori T.,Kuo SC
  • Journal Title: Bioorg Med Chem 13(1) Pages: 265-75
• [Journal Article] New bisindole alkaloids isolated from Myxomycetes Arcyria cinerea and Lycogala epidendrum (2005)
  • Author(s): Kamata K, Kiyota M, Naoe A, Nakatani S, Yamamoto Y, Hayashi M, Komiyama K, Yamori T, Ishibashi M
  • Journal Title: Chemical & pharmaceutical bulletin 53(5) Pages: 594-7
• [Journal Article] Antitumor effect of cotylenin A plus interferon-alpha : Possible therapeutic agents against ovary carcinoma (2005)
  • Author(s): Honma Y, Kasukabe T, Yamori T, Kato N, Sassa T
  • Journal Title: Gynecol 0ncol 99(3) Pages: 680-8
• [Presentation] がん細胞による化合物プロフィルの描出法(Cancer Cell lnformatics) : 方法論から分子標的薬開発への応用まで (2009)
  • Author(s): 矢守隆夫
  • Organizer: 第2回和漢薬の科学研究シンポジウム
  • Place of Presentation: 富山
  • Year and Date: 20090000
• [Presentation] PT3キナーゼ阻害剤の開発 (2009)
  • Author(s): 矢守隆夫
  • Organizer: 第7回日本臨床腫瘍学会
  • Place of Presentation: 名古屋
  • Year and Date: 20090000
• [Presentation] Evaluation of antitumor activity of a novel PI3K inhibitor ZSTK474 by various human cancer xenograft models (2008)
  • Author(s): Yamori T, 0kamura M
  • Organizer: The20th EORTC-NCI-AACR symposium
  • Place of Presentation: Geneva, Switzerland
  • Year and Date: 20080000
• [Presentation] Antitumor Effect of a PI3-Kinase Inhibitor ZSTK474 in an Orthotopic Brain Tumor Model (2008)
  • Author(s): Yamori T, 0kamura M, Yoshimi H, Yaguchi S, Kawada M
  • Organizer: Targeting the PI3-Kinase Pathway in Cancer(AACR Specia1 Conferences)
  • Place of Presentation: Cambridge, Massachusetts, USA
  • Year and Date: 20080000
• [Presentation] A New PI3 Kinase Inhibitor ZSTK 474 identified by JFCR39 Cancer Cell Pane (2008)
  • Author(s): Yamori T
  • Organizer: The 22nd Naito Conference on Chemica1 Biology[I]
  • Place of Presentation: Sapporo
  • Year and Date: 20080000
• [Presentation] アカデミアにおける分子標的-薬探索の試み (2008)
  • Author(s): 矢守隆夫
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 20080000
• [Presentation] Identification of candidates for new drug, target and biomarker by mining data sets from a panel of human cancer cell lines : JFCR39 (2007)
  • Author(s): Yamori T
  • Organizer: MBI Chemogenomics Workshop
  • Place of Presentation: Ohio, USA
  • Year and Date: 20070000
• [Presentation] Informatics-guided identification of candidates for new drug, target and biomarker based on JFCR39 (2007)
  • Author(s): Yamori T
  • Organizer: 66-th Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: Yokohama
  • Year and Date: 20070000
• [Presentation] Cancer Cell Informatics による分子標的同定 (2007)
  • Author(s): 矢守隆夫
  • Organizer: 日本薬理学会・シンポジウム
  • Place of Presentation: 名古屋
  • Year and Date: 20070000
• [Presentation] PI3キナーゼを分子標的にした新しいがん治療法の開発 (2006)
  • Author(s): 矢守隆夫
  • Organizer: 文部科学省科学研究費補助金「特定領域研究」がん研究に係わる特定領域研究・公開シンポジウム
  • Place of Presentation: 東京
  • Year and Date: 20060000
• [Book] Mebio Oncology, 5(1) (2008)
  • Author(s): 矢守隆夫
  • Total Pages: 18-28
  • Publisher: Cancer Cell Informatics の活用と分子標的薬の探索評価
• [Book] 蛋白質核酸酵素, 52(13) (2007)
  • Author(s): 矢守隆夫
  • Total Pages: 1690-5
  • Publisher: Cancer Cell Informaticsとケミカルバイオロジー
• [Patent(Industrial Property Rights)] PI3キナーゼ阻害剤の効果判定法 (2007)
  • Inventor(s): 明石哲行、矢守隆夫、岡村睦美
  • Industrial Property Rights Holder: 財団法人癌研究会
  • Industrial Property Number: 特願, 2007-218234
  • Filing Date: 2007-08-24
• [Patent(Industrial Property Rights)] PI3キナーゼ阻害剤に対する感受性予測方法 (2006)
  • Inventor(s): 明石哲行、西村由美子、矢守隆夫
  • Industrial Property Rights Holder: 財団法人癌研究会
  • Industrial Property Number: 特願, 2006-221146
  • Filing Date: 2006-08-14
• [Patent(Industrial Property Rights)] PI3キナーゼ阻害剤の効果判定法 (2006)
  • Inventor(s): 且慎吾、矢守隆夫
  • Industrial Property Rights Holder: -財-団法人癌研究会
  • Industrial Property Number: 特願, 2006-229568
  • Filing Date: 2006-08-25