Development of anti-cancer agents targeting the endocytic pathway

• Project/Area Number: 22681034
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Living organism molecular science
• Research Institution: The Institute of Physical and Chemical Research
• Principal Investigator: KAWATANI Makoto 独立行政法人理化学研究所, 化合物ライブラリー評価研究チーム, 専任研究員 (50391925)
• Research Collaborator: MUROI Makoto 独立行政法人理化学研究所, 化合物ライブラリー評価研究チーム, 専任研究員 (30261168) ; FUTAMURA Yushi 独立行政法人理化学研究所, 化学情報・化合物創製チーム, 協力研究員 (70525857) ; KAZAMI Sayaka 独立行政法人理化学研究所, 化合物ライブラリー評価研究チーム, 協力技術員 ; HONDA Kaori 独立行政法人理化学研究所, 化合物ライブラリー評価研究チーム, 協力技術員
• Project Period (FY): 2010 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥23,400,000 (Direct Cost: ¥18,000,000、Indirect Cost: ¥5,400,000); Fiscal Year 2012: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2011: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2010: ¥12,480,000 (Direct Cost: ¥9,600,000、Indirect Cost: ¥2,880,000)
• Keywords: 癌 / 小分子化合物 / エンドサイトーシス

Research Abstract

The purpose of this study is to construct a cell morphology-based high-content screening system and to develop anti-cancer agents targeting the endocytic pathway. We constructed a chemical-genetic phenotype profiling system based on the high-content cell morphology database, Morphobase. We showed that NPD1801, which perturbs the endocytic pathway, targeted calmodulin, caused the activation of Ras-Raf pathway, the inhibition of the fusion of late endosome and lysosome, and the dysfunction of lysosome, and resulted in the cancer cell death.

Research Products

• [Journal Article] Dual structure-activity relationship of osteoclastogenesis inhibitor methyl gerfelin based on TEG scanning. (2013)
  • Author(s): Kanoh N., Suzuki T., Kawatani M., Katou Y., Oshima Y., Osada H., and Iwabuchi Y.
  • Journal Title: Bioconjug. Chem. Volume: 24 Pages: 44-52
• [Journal Article] Isolation of new polyketide metabolites, linearolides A and B, from a Streptomyces sp. RK95-74 (2013)
  • Author(s): Ueki M. et al.
  • Journal Title: J. Antibiot. Volume: - Issue: 6 Pages: 333-337
  • DOI: 10.1038/ja.2013.19
  • Peer Reviewed
• [Journal Article] Dual Structure-Activity Relationship of Osteoclastogenesis Inhibitor Methyl Gerfelin Based on TEG Scanning (2013)
  • Author(s): Kanoh, N.
  • Journal Title: Bioconjugate Chem. Volume: 24 Issue: 1 Pages: 44-52
  • DOI: 10.1021/bc3003666
  • Peer Reviewed
• [Journal Article] Creation of novel reveromycin derivatives by alcohol added fermentation (2013)
  • Author(s): Nogawa T. et al.
  • Journal Title: J. Antibiot. Volume: 66 Issue: 4 Pages: 247-250
  • DOI: 10.1038/ja.2012.115
  • Peer Reviewed
• [Journal Article] Morphobase, an encyclopedic cell morphology database, and its use for drug target identification. (2012)
  • Author(s): Futamura Y., Kawatani M., Kazami S., Tanaka K., Muroi M., Shimizu T., Tomita K., Watanabe N., and Osada H.
  • Journal Title: Chem. Biol. Volume: 19 Pages: 1620-1630
• [Journal Article] Violaceols function as actin inhibitors inducing cell shape elongation in fibroblast cells. (2012)
  • Author(s): Asami Y., Jang J.-H., Oh H., Sohn J. H., Kim J. W., Moon D. O., Kwon O., Kawatani M., Osada H., Kim B. Y., and Ahn J. S.
  • Journal Title: Biosci. Biotechnol. Biochem. Volume: 76 Pages: 1431-1437
  • NAID: 10031065548
• [Journal Article] Effect of reveromycin A on experimental tooth movement in OPG-/- mice. (2012)
  • Author(s): Tanaka M., Miyazawa K., Tabuchi M., Yabumoto T., Kadota M., Yoshizako M., Yamane C., Kawatani M., Osada H., Maeda H., and Goto S.
  • Journal Title: J. Dent. Res. Volume: 91 Pages: 771-776
• [Journal Article] Protein disulfide isomerase-mediated disulfide bonds regulate the gelatinolytic activity and secretion of matrix metalloproteinase-9. (2012)
  • Author(s): Khan M. M., Simizu S., Suzuki T., Masuda, A., Kawatani M., Muroi M., Dohmae N., and Osada H.
  • Journal Title: Exp. Cell Res. Volume: 318 Pages: 904-914
• [Journal Article] Spirotoamides A and B, novel 6,6-spiroacetal polyketides isolated from a microbial metabolite fraction library. (2012)
  • Author(s): Nogawa T., Takahashi S., Okano A., Kawatani M., Uramoto M., Saito T., and Osada H.
  • Journal Title: J. Antibiot. Volume: 65 Pages: 123-128
  • NAID: 10030711040
• [Journal Article] The potential of protein disulfide isomerase as a therapeutic drug target. (2012)
  • Author(s): Khan M. M., Simizu S., Kawatani M., and Osada H.
  • Journal Title: Oncol. Res. Volume: 19 Pages: 445-453
• [Journal Article] Violaceols function as actin inhibitors inducing cell shape elongation in fibroblast cells (2012)
  • Author(s): Asami Y. et al.
  • Journal Title: Biosci. Biotechnol. Biochem. Volume: 76 Pages: 1431-1437
  • Peer Reviewed
• [Journal Article] Effect of Reveromycin A on Experimental Tooth Movement in OPG-/- Mice． (2012)
  • Author(s): Tanaka M, Miyazawa K, Tabuchi M, Yabumoto T, Kadota M, Yoshizako M, Yamane C, Kawatani M, Osada H, Maeda H, Goto S
  • Journal Title: Journal of Dental Research Volume: 91(8) Issue: 8 Pages: 771-776
  • DOI: 10.1177/0022034512451026
  • Peer Reviewed
• [Journal Article] Protein disulfide isomerase-mediated disulfide bonds regulate the gelatinolytic activity and secretion of matrix metalloproteinase-9 (2012)
  • Author(s): Khan, M. G. M., Simizu, S., Suzuki, T., Masuda, A., Muroi, M., Kawatani, M., Dohmae, N. & Osada, H
  • Journal Title: Experimental Cell Research Volume: 318 Issue: 8 Pages: 904-914
  • DOI: 10.1016/j.yexcr.2012.02.021
  • Peer Reviewed
• [Journal Article] Spirotoamides A and B, novel 6,6-spiroacetal polyketides isolated from a microbial metabolite fraction library (2012)
  • Author(s): Nogawa T
  • Journal Title: J.Antibiot. Volume: (In press) Issue: 3 Pages: 123-128
  • DOI: 10.1038/ja.2011.121
  • Peer Reviewed
• [Journal Article] Identification of a small-molecule inhibitor of DNA topoisomerase II by proteomic profiling. (2011)
  • Author(s): Kawatani M., Takayama H., Muroi M., Kimura S., Maekawa T., and Osada H.
  • Journal Title: Chem. Biol. Volume: 18 Pages: 743-751
• [Journal Article] Genetic safeguard against mycotoxin cyclopiazonic acid production in Aspergillus oryzae. (2011)
  • Author(s): Kato N., Tokuoka M., Shinohara Y., Kawatani M., Uramoto M., Seshime Y., Fujii I., Kitamoto K., Takahashi T., Takahashi S., Koyama Y., and Osada, H.
  • Journal Title: Chembiochem Volume: 12 Pages: 1376-1382
• [Journal Article] Discovery of a small molecule PDI inhibitor that inhibits reduction of HIV-1 envelope glycoprotein gp120. (2011)
  • Author(s): Khan M. M., Simizu S., Lai N. S., Kawatani M., Shimizu T., and Osada H.
  • Journal Title: ACS Chem. Biol. Volume: 6 Pages: 245-251
• [Journal Article] Morphobase, an encyclopedic cell morphology database, and its use for drug target identification. (2011)
  • Author(s): Futamura, Y., et al.
  • Journal Title: Chem Biol. Volume: 19 Issue: 12 Pages: 1620-1630
  • DOI: 10.1016/j.chembiol.2012.10.014
  • Peer Reviewed
• [Journal Article] Identification of a small-molecule inhibitor of DNA topoisomerase II by proteomic profiling (2011)
  • Author(s): Kawatani M., et al
  • Journal Title: Chem.Biol. Volume: 18 Issue: 6 Pages: 743-751
  • DOI: 10.1016/j.chembiol.2011.03.012
  • Peer Reviewed
• [Journal Article] Genetic safeguard against mycotoxin cyclopiazonic acid production in Aspergillus oryzae (2011)
  • Author(s): Kato N
  • Journal Title: ChemBioChem. Volume: 12 Issue: 9 Pages: 1376-1382
  • DOI: 10.1002/cbic.201000672
  • Peer Reviewed
• [Journal Article] Application of proteomic profiling based on 2D-DIGE for classification of compounds according to the mechanism of action. (2010)
  • Author(s): Muroi M., Kazami S., Noda K., Kondo H., Takayama H., Kawatani M., Usui T., and Osada H.
  • Journal Title: Chem. Biol. Volume: 17 Pages: 460-470
  • NAID: 120007137992
• [Journal Article] Glyoxalase-I is a novel target against Bcr-Abl+ leukemic cells acquiring stem-like characteristics in hypoxic environment. (2010)
  • Author(s): Takeuchi M., Kimura S., Kuroda J., Ashihara E., Kawatani M., Osada H., Umezawa K., Yasui E., Imoto M., Tsuruo T., Yokota A., Tanaka R., Nagao R., Nakahata T., Fujiyama Y., and Maekawa T.
  • Journal Title: Cell Death Diff. Volume: 17 Pages: 1211-1220
• [Journal Article] Application of proteomic profiling based on 2D-DIGE for classification of compounds according to the mechanism of action (2010)
  • Author(s): Muroi, M., et al.
  • Journal Title: Chem.Biol. Volume: 17 Pages: 460-470
  • NAID: 120007137992
  • Peer Reviewed
• [Journal Article] Glyoxalase-I is a novel target against Bcr-Abl+ leukemic cells acquiring stem-like characteristics in hypoxic environment (2010)
  • Author(s): Takeuchi, M., et al.
  • Journal Title: Cell Death Diff. Volume: 17 Pages: 1211-1220
  • Peer Reviewed
• [Journal Article] Isolation of new polyketide metabolites, linearolides A and B, from a Streptomyces sp. RK95-74.
  • Author(s): Ueki M., Koshiro N., Aono H., Kawatani M., Uramoto M., Kawasaki H., and Osada H.
  • Journal Title: J. Antibiot. Volume: (in press)
  • NAID: 10031183840
• [Journal Article] Creation of novel reveromycin derivatives by alcohol added fermentation.
  • Author(s): Nogawa T., Takahashi S., Sekiyama Y., Takagi H., Uramoto M., Koshino H., Kawatani M., Shimizu T., and Osada H.
  • Journal Title: J. Antibiot. Volume: (in press)
  • NAID: 10031168688
• [Journal Article] The potential of protein disulfide isomerase as a therapeutic drug target
  • Author(s): Khan M.M., et al
  • Journal Title: Oncol.Res. Volume: (印刷中)
  • Peer Reviewed
• [Journal Article] Discovery of a small molecule PDI inhibitor that inhibits reduction of HIV-1 envelope glycoprotein gp120
  • Author(s): Khan, M.M., et al.
  • Journal Title: ACS Chem.Biol. Volume: (印刷中)
  • Peer Reviewed
• [Presentation] 破骨細胞を標的とする小分子化合物の化学遺伝学的解析 (2012)
  • Author(s): 川谷誠、長田裕之
  • Organizer: 第153回日本獣医学会学術集会
  • Place of Presentation: 大宮ソニックシティ(大宮)(招待講演)
  • Year and Date: 2012-03-28
• [Presentation] 破骨細胞を標的とする小分子化合物の化学遺伝学的解析 (2012)
  • Author(s): 川谷誠、長田裕之
  • Organizer: 第153回日本獣医学会学術集会
  • Place of Presentation: 大宮
  • Year and Date: 2012-03-27
• [Presentation] Proteome- and cell morphology-based target identification for RKB3564F070, a new cytotoxic fungal metabolite (2012)
  • Author(s): Makoto Kawatani, Harumi Aono, Toshihiko Nogawa, Makoto Muroi, Yushi Futamura, and Hiroyuki Osada
  • Organizer: The 1st official conference of the international chemical biology society
  • Place of Presentation: Boston, USA
• [Presentation] Chemical biology studies on inhibitors of cancer bone metastases (2012)
  • Author(s): 川谷誠
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌
• [Presentation] Identification of a molecular target for RKB3564F070, a new cytotoxic fungal metabolite (2012)
  • Author(s): 川谷誠、青野晴美、室井誠、二村友史、長田裕之
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌
• [Presentation] Identification of novel tubulin polymerization inhibitors by proteomic profiling (2012)
  • Author(s): Makoto Kawatani, Makoto Muroi, and Hiroyuki Osada
  • Organizer: The 16th JFCR-ISCC
  • Place of Presentation: Tokyo, Japan
• [Presentation] Identification of novel tubulin polymerization inhibitors by proteomic profiling (2012)
  • Author(s): Kawatani M., et al
  • Organizer: The 16th JFCR-ISCC
  • Place of Presentation: Miraikan (Tokyo)
• [Presentation] Identification of novel tubulin polymerization inhibitors by proteomic profiling (2011)
  • Author(s): Makoto Kawatani, Kouji Tomita, Makoto Muroi, Sayaka Kazami, Harumi Aono, Takeshi Shimizu, and Hiroyuki Osada
  • Organizer: AACR-NCI-EORTC International Conference "Molecular Targets and Cancer Therapeutics"
  • Place of Presentation: San Francisco, USA
• [Presentation] プロテオームプロファイリングによるチューブリン重合阻害剤の同定 (2011)
  • Author(s): 川谷誠、青野晴美、室井誠、長田裕之
  • Organizer: 第70回日本癌学会学術集会
  • Place of Presentation: 名古屋
• [Presentation] プロテオームプロファイリングによるチューブリン重合阻害剤の同定 (2011)
  • Author(s): 川谷誠、富田康司、風見紗弥香、青野晴美、室井誠、清水猛、長田裕之
  • Organizer: 第15回日本がん分子標的治療学会学術集会
  • Place of Presentation: 東京
• [Presentation] Identification of novel tubulin polymerization inhibitors by proteomic profiling (2011)
  • Author(s): Kawatani M., et al
  • Organizer: AACR-NCI-EORTC International Conference "Molecular Targets and Cancer Therapeutics"
  • Place of Presentation: Moscone Center West (San Francisco)
• [Presentation] プロテオームプロファイリングによるチューブリン重合阻害剤の同定 (2011)
  • Author(s): 川谷誠, ら
  • Organizer: 第70回日本癌学会学術集会
  • Place of Presentation: 名古屋国際会議場(名古屋)
• [Presentation] Antitumor activity of NPD723, a novel potent cell differentiation-inducing agent in leukemic cells (2010)
  • Author(s): Makoto Kawatani, Harumi Aono, and Hiroyuki Osada
  • Organizer: 22nd AACR-NCI-EORTC International Conference "Molecular Targets and Cancer Therapeutics"
  • Place of Presentation: Berlin, Germany
• [Presentation] The identification of a novel inhibitor of osteoclastogenesis that acts via inhibition of glyoxalase I (2010)
  • Author(s): Makoto Kawatani, and Hiroyuki Osada
  • Organizer: 2010 RIKEN Chemical Biology International Symposium
  • Place of Presentation: Saitama, Japan
• [Presentation] 細胞質空胞化を誘導するNPD1801 の作用機作解析 (2010)
  • Author(s): 川谷誠、青野晴美、早川洋一、長田裕之
  • Organizer: 第69回日本癌学会学術総会
  • Place of Presentation: 大阪
• [Presentation] 細胞質空胞化を誘導するNPD1801 の作用機構解析 (2010)
  • Author(s): 川谷誠、風見紗弥香、青野晴美、早川洋一、長田裕之
  • Organizer: 第14回日本がん分子標的治療学会学術集会
  • Place of Presentation: 東京
• [Presentation] Antitumor activity of NPD723, a novel potent cell differentiation-inducing agent in leukemic cells (2010)
  • Author(s): Kawatani, M., et al.
  • Organizer: 22nd AACR-NCI-EORTC International Conference "Molecular Targets and Cancer Therapeutics"
  • Place of Presentation: Berlin
• [Presentation] The identification of a novel inhibitor of osteoclastogenesis that acts via inhibition of glyoxalase I (2010)
  • Author(s): Kawatani, M., et al.
  • Organizer: 2010 RIKEN Chemical Biology International Symposium
  • Place of Presentation: 埼玉
• [Presentation] 細胞質空胞化を誘導するNPD1801の作用機作解析 (2010)
  • Author(s): 川谷誠, ら
  • Organizer: 第69回日本癌学会学術総会
  • Place of Presentation: 大阪
• [Presentation] 細胞質空胞化を誘導するNPD1801の作用機構解析 (2010)
  • Author(s): 川谷誠, ら
  • Organizer: 第14回日本がん分子標的治療学会学術集会
  • Place of Presentation: 東京
• [Book] 「細胞骨格系」日本臨床(増刊号) (2012)
  • Author(s): 川谷誠、長田裕之
• [Book] 細胞骨格系、分子標的薬 －がんから他疾患までの治癒をめざして－ (2012)
  • Author(s): 川谷誠 他
  • Publisher: 日本臨牀社