Anticancer drug discovery based on regulation of chromatin structure and function

2009 Fiscal Year Final Research Report

• Project/Area Number: 17016080
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: The Institute of Physical and Chemical Research
• Principal Investigator: YOSHIDA Minoru The Institute of Physical and Chemical Research, 吉田化学遺伝学研究室, 主任研究員 (80191617)
• Co-Investigator(Kenkyū-buntansha): YASHIRODA Yoko 独立行政法人理化学研究所, 吉田化学遺伝学研究室, 専任研究員 (60360658) ; NISHINO Norikazu 九州工業大学, 大学院・生命体工学研究科, 教授 (40145165)
• Co-Investigator(Renkei-kenkyūsha): YANORI Takao 財団法人癌研究会, 癌化学療法センター分子薬理部, 部長 (60200854)
• Project Period (FY): 2005 – 2009
• Keywords: ヒストン / アセチル化 / メチル化 / SUMO化 / ケミカルゲノミクス / ドラックデザイン / スプライシング / エピジェネティクス

Research Abstract

It has been shown that regulation of chromatin structure and function including histone acetylation is involved in tumorigenesis. In this study, we aimed to identify factors responsible for chromatin regulation and develop their inhibitors. We succeeded in developing Ky-2, a new HDAC inhibitor exhibiting strong antitumor activity, the first splicing inhibitor spliceostatin A that affects chromatin structure, and a novel fluorescent imaging probe that allows detection of histone acetylation in living cells.

Research Products

• [Journal Article] Bicyclic peptides as potent inhibitors of histone deacetylases: Optimization of alkyl loop length. (2010)
  • Author(s): Islam, N.M., Kato, T., Nishino, N., Kim, H. -J., Ito, A., Yoshida, M.
  • Journal Title: Bioorg. Med. Chem. Lett. 20 Pages: 997-999
  • Peer Reviewed
• [Journal Article] Garbled messages and corrupted translations. (2010)
  • Author(s): Schneider-Poetsch, T., Usui, T., Kaida, D., Yoshida, M.
  • Journal Title: Nature Chem. Biol. 6 Pages: 189-198
  • Peer Reviewed
• [Journal Article] Total synthesis of the bicyclic depsipeptide HDAC inhibitors spiruchostatins A and B, 5''-epi-spiruchostatin B, FK228 (FR901228) and preliminary evaluation of their biological activity. (2009)
  • Author(s): Narita, K., Kikuchi, T., Watanabe, K., Takizawa, T., Oguchi, T., Kudo, K., Matsuhara, K., Abe, H., Yamori, T., Yoshida, M., Katoh, T.
  • Journal Title: Chemistry 15 Pages: 11174-11186
  • Peer Reviewed
• [Journal Article] Real-time imaging of histone H4 hyperacetylation in living cells. (2009)
  • Author(s): Sasaki, K., Ito, T., Nishino, N., Khochbin, S., Yoshida, M.
  • Journal Title: Proc. Natl. Acad. Sci. U.S.A. 106 Pages: 16257-16262
  • Peer Reviewed
• [Journal Article] JBIR-17, a novel trichostatin analogue from Streptomyces sp. 26634. (2009)
  • Author(s): Ueda, J. -y., Hwang, J. -H., Kato, T., Ochiai, A., Isshiki, K., Yoshida, M., Takagi, M., Shin-ya, K.
  • Journal Title: J. Antibiotics 62 Pages: 283-285
  • Peer Reviewed
• [Journal Article] The protein farnesyltransferase regulates HDAC6 activity in a microtubule-dependent manner. (2009)
  • Author(s): Zhou, J., Vos, C.C., Gjyrezi, A., Yoshida, M., Khuri, F.R., Tamanoi, F., Giannakakou, P.
  • Journal Title: J. Biol. Chem. 284 Pages: 9648-9655
  • Peer Reviewed
• [Journal Article] New Rev-export inhibitor from Alpinia galanga and structure-activity relationship. (2009)
  • Author(s): Tamura, S., Shiomi, A., Kaneko, M., Ye, Y., Yoshida, M., Yoshikawa, M., Kimura, T., Kobayashi, M., Murakami, N.
  • Journal Title: Bioorg. Med. Chem. Lett. 19 Pages: 2555-2557
  • Peer Reviewed
• [Journal Article] A molecular barcoded yeast ORF library enables mode-of-action analysis of bioactive compounds. (2009)
  • Author(s): Ho, C.H., Magtanong, L., Barker, S.L., Gresham, D., Nishimura, S., Natarajan, P., Koh, J.L.Y., Proter, J., Gray, C.A., Andersen, R.J., Giaever, G., Nislow, C., Andrews, B., Botstein, D., Graham, T.R., Yoshida, M., Boone, C.
  • Journal Title: Nature Biotechnol. 27 Pages: 369-377
  • Peer Reviewed
• [Journal Article] Ginkgolic acid inhibits protein SUMOylation by blocking formation of the E1-SUMO intermediate. (2009)
  • Author(s): Fukuda, I., Ito, A., Hirai, G., Nishimura, S., Kawasaki, H., Saitoh, H., Kimura, K. -i., Sodeoka, M., Yoshida, M.
  • Journal Title: Chem. Biol. 16 Pages: 133-140
  • Peer Reviewed
• [Journal Article] Kerriamycin B inhibits protein SUMOylation. (2009)
  • Author(s): Fukuda, I., Ito, A., Uramoto, M., Saitoh, H., Kawasaki, H., Osada, H., Yoshida, M.
  • Journal Title: J. Antibiotics 62 Pages: 221-224
  • Peer Reviewed
• [Journal Article] Interaction of aliphatic cap group in inhibition of histone deacetylases by cyclic tetrapeptides. (2008)
  • Author(s): Nishino, N., Shivashimpi, G.M., Soni, P.B., Bhuiyan, M.P.I., Kato, T., Maeda, S., Nishino, T.G., Yoshida, M.
  • Journal Title: Bioorg. Med. Chem. 16 Pages: 437-445
  • Peer Reviewed
• [Journal Article] HDAC6 a new cellular stress surveillance factor. (2008)
  • Author(s): Matthias, P., Yoshida, M., Khochbin, S.
  • Journal Title: Cell Cycle 7 Pages: 7-10
  • Peer Reviewed
• [Journal Article] Evaluation of antiangiogenic activity of azumamides by the in vitro vascular organization model using mouse-induced pluripotent stem (iPS) cells. (2008)
  • Author(s): Nakao, Y., Narazaki, G., Hoshino, T., Maeda, S., Yoshida, M., Maejima, H., Yamashita, J.K.
  • Journal Title: Bioorg. Med. Chem. Lett. 18 Pages: 2982-2984
  • Peer Reviewed
• [Journal Article] Bach1 inhibits oxidative stress-induced cellular senescence by impeding p53 function on chromatin. Nature Struct. (2008)
  • Author(s): Dohi, Y., Ikura, T., Hoshikawa, Y., Katoh, Y., Ota, K., Nakanome, A., Muto, A., Omura, S., Ohta, T., Ito, A., Yoshida, M., Noda, T., Igarashi, K.
  • Journal Title: Mol. Biol. 15 Pages: 1246-1254
  • Peer Reviewed
• [Journal Article] Characterisation of the in vitro activity of the depsipeptide histone deacetylase inhibitor spiruchostatin A. (2008)
  • Author(s): Crabb, S.J., Howell, M., Rogers, H., Ishfaq, M., Yurek-George, A., Carey, K., Pickering, B.M., East, P., Mitter, R., Maeda, S., Johnson, P.W., Townsend, P., Shin-ya, K., Yoshida, M., Ganesan, A., Packham, G.
  • Journal Title: Biochem. Pharmacol. 76 Pages: 463-475
  • Peer Reviewed
• [Journal Article] Combined effects of p53 gene therapy and leptomycin B in human esophageal squamous cell carcinoma. (2008)
  • Author(s): Hoshino, I., Matsubara, H., Komatsu, A., Akutsu, Y., Nishimori, T., Yoneyama, Y., Murakami, K., Sakata, H., Matsushita, K., Miyazawa, Y., Brooks, R., Yoshida, M., Ochiai, T.
  • Journal Title: Oncology 75 Pages: 113-119
  • Peer Reviewed
• [Journal Article] Effects of downregulated HDAC6 expression on the proliferation of lung cancer cells. Biochem. (2008)
  • Author(s): Kamemura, K., Ito, A., Shimazu, T., Matsuyama, A., Maeda, S., Yao, T. -P., Horinouchi, S., Khochbin, S., Yoshida, M.
  • Journal Title: Biophys. Res. Commun. 374 Pages: 84-89
  • Peer Reviewed
• [Journal Article] 14-3-3 regulates the nuclear import of class IIa histone deacetylases. (2008)
  • Author(s): Nishino, T.G., Miyazaki, M., Hoshino, H., Miwa, Y., Horinouchi, S., Yoshida, M.
  • Journal Title: Biochem. Biophys. Res. Commun. 377 Pages: 852-856
  • Peer Reviewed
• [Journal Article] Inhibition of splicing and nuclear retention of pre-mRNA by spliceostatin A in fission yeast. (2007)
  • Author(s): Lo, C. -W., Kaida, D., Nishimura, S., Matsuyama, A., Yashiroda, Y., Taoka, H., Ishigami, K., Watanabe, H., Nakajima, H., Tani, T., Horinouchi, S., Yoshida, M.
  • Journal Title: Biochem. Biophys. Res. Commun. 364 Pages: 573-577
  • Peer Reviewed
• [Journal Article] Multiple histone deacetylases and the CREB-binding protein regulate pre-mRNA 3'-end processing. (2007)
  • Author(s): Shimazu, T., Horinouchi, S., Yoshida, M.
  • Journal Title: J. Biol. Chem. 282 Pages: 4470-4478
  • Peer Reviewed
• [Journal Article] Involvement of protein phosphatase 2A nuclear accumulation and subsequent inactivation of activator protein-1 in leptomycin B-inhibited cyclin D1 expression. (2007)
  • Author(s): Tsuchiya, A., Tashiro, E., Yoshida, M., Imoto, M.
  • Journal Title: Oncogene 26 Pages: 1522-1532
  • Peer Reviewed
• [Journal Article] Molecular design of histone deacetylase inhibitors by aromatic ring shifting in chlamydocin framework. (2007)
  • Author(s): Shivashimpi, G.M., Amagai, S., Kato, T., Nishino, N., Maeda, S., Nishino, T.G., Yoshida, M.
  • Journal Title: Bioorg. Med. Chem. 15 Pages: 7830-7839
  • Peer Reviewed
• [Journal Article] Design, synthesis, and evaluation of isoindolinone-hydroxamic acid derivatives as histone deacetylase (HDAC) inhibitors. (2007)
  • Author(s): Lee, S., Shinji, C., Ogura, K., Shimizu, M., Maeda, S., Sato, M., Yoshida, M., Hashimoto, Y., Miyachi, H.
  • Journal Title: Bioorg. Med. Chem. Lett. 17 Pages: 4895-4900
  • Peer Reviewed
• [Journal Article] Spliceostatin A targets SF3b and inhibits both splicing and nuclear retention of pre-mRNA. (2007)
  • Author(s): Kaida, D., Motoyoshi, H., Tashiro, E., Nojima, T., Hagiwara, M., Ishigami, K., Watanabe, H., Kitahara, T., Yoshida, T., Nakajima, H., Tani, T., Horinouchi, S., Yoshida, M.
  • Journal Title: Nature Chem. Biol. 3 Pages: 576-583
  • Peer Reviewed
• [Journal Article] The first biologically active synthetic analogues of FK228, the depsipeptide histone deacetylase inhibitor. (2007)
  • Author(s): Yurek-George, A., Cecil, A.R.L., Mo, A.H.K., Wen, S., Rogers, H., Habens, F., Maeda, S., Yoshida, M., Packham, G., Ganesan, A.
  • Journal Title: J. Med. Chem. 50 Pages: 5720-5726
  • Peer Reviewed
• [Journal Article] Corepressor SMRT and class II histone deacetylases promote Bach2 nuclear retention and formation of nuclear foci that are responsible for local transcriptional repression. (2007)
  • Author(s): Hoshino, H., Nishino, T.G., Tashiro, S., Miyazaki, M., Ohmiya, Y., Igarashi, K., Horinouchi, S., Yoshida, M.
  • Journal Title: J. Biochem. (Tokyo) 141 Pages: 719-727
  • Peer Reviewed
• [Journal Article] Bone morphogenetic protein-2 stimulates Runx2 acetylation. (2006)
  • Author(s): Jeon, E. -J., Lee, K. -Y., Choi, N. -S., Lee, M. -H., Kim, H. -N., Jin, Y. -H., Ryoo, H. -M., Choi, J. -Y., Yoshida, M., Nishino, N., Oh, B. -C., Lee, K. -S., Lee, Y.H., Bae, S. -C.
  • Journal Title: J. Biol. Chem. 281 Pages: 16502-16511
  • Peer Reviewed
• [Journal Article] Nucleolin is involved in interferon Regulatory Factor-2 dependent transcriptional activation. (2006)
  • Author(s): Masumi, A., Fukazawa, H., Shimazu, T., Yoshida, M., Ozato, K., Komuro, K., Yamaguchi, K.
  • Journal Title: Oncogene 25 Pages: 5113-5124
  • Peer Reviewed
• [Journal Article] Regulation of SV40 large T antigen stability by reversible acetylation. (2006)
  • Author(s): Shimazu, T., Komatsu, Y., Nakayama, K.I., Fukazawa, H., Horinouchi, S., Yoshida, M.
  • Journal Title: Oncogene 25 Pages: 7391-7400
  • Peer Reviewed
• [Journal Article] ORFeome cloning and global analysis of protein localization in the fission yeast Schizosaccharomyces pombe. (2006)
  • Author(s): Matsuyama, A., Arai, R., Yashiroda, Y., Shirai, A., Kamata, A., Sekido, S., Kobayashi, Y., Hashimoto, A., Hamamoto, M., Hiraoka, Y., Horinouchi, S., Yoshida, M.
  • Journal Title: Nature Biotechnol. 24 Pages: 841-847
  • Peer Reviewed
• [Journal Article] Nucleocytoplasmic transport of fluorescent mRNA in living mammalian cells: nuclear mRNA export is coupled to ongoing gene transcription. (2006)
  • Author(s): Tokunaga, K., Shibuya, T., Ishihama, Y., Tadakuma, H., Ide, M., Yoshida, M., Funatsu, T., Ohshima, Y., Tani, T.
  • Journal Title: Genes Cells 11 Pages: 305-317
  • Peer Reviewed
• [Journal Article] Chlamydocin analogs bearing carbonyl group as possible ligand toward zinc atom in histone deacetylases. (2006)
  • Author(s): Bhuiyan, M.P., Kato, T., Okauchi, T., Nishino, N., Maeda, S., Nishino, T.G., Yoshida, M.
  • Journal Title: Bioorg. Med. Chem. 14 Pages: 3438-3446
  • Peer Reviewed
• [Journal Article] Induction of a ribotoxic stress response that stimulates stress-activated protein kinases by 13-deoxytedanolide, an antitumor marine macrolide. Biosci. (2006)
  • Author(s): Lee, K. -H., Nishimura, S., Matsunaga, S., Fusetani, N., Ichijo, H., Horinouchi, S., Yoshida, M.
  • Journal Title: Biotechnol. Biochem. 69 Pages: 161-171
  • Peer Reviewed
• [Journal Article] Design, synthesis, and evaluation of cyclic amide/imide-bearing hydroxamic acid derivatives as class-selective histone deacetylase (HDAC) inhibitors. (2006)
  • Author(s): Shinji, C., Maeda, S., Imai, K., Yoshida, M., Hashimoto, Y., Miyachi, H.
  • Journal Title: Bioorg Med Chem. 14 Pages: 7625-7651
  • Peer Reviewed
• [Journal Article] Highly potent and selective histone deacetylase 6 inhibitors designed based on a small-molecular substrate. (2006)
  • Author(s): Suzuki, T., Kouketsu, A., Itoh, Y., Hisakawa, S., Maeda, S., Yoshida, M., Nakagawa, H., Miyata, N.
  • Journal Title: J Med. Chem. 49 Pages: 4809-4812
  • Peer Reviewed
• [Journal Article] Sichuan pepper extracts block the PAK1/Cyclin D1 pathway and the growth of NF1-deficient cancer xenograft in mice. (2006)
  • Author(s): Hirokawa, Y., Nheu, T., Grimm, K., Mautner, V., Maeda, S., Yoshida, M., Komiyama, K., Maruta, H.
  • Journal Title: Cancer Biol Ther 5 Pages: 305-309
  • Peer Reviewed
• [Journal Article] Nuclear-cytoplasmic shuttling of a RING-IBR protein RBCK1 and its functional interaction with nuclear body proteins. (2005)
  • Author(s): Tatematsu, K., Yoshimoto, N., Koyanagi, T., Tokunaga, C., Tachibana, T., Yoneda, Y., Yoshida, M., Okajima, T., Tanizawa, K., Kuroda, S. i.
  • Journal Title: . Biol. Chem. 280 Pages: 22937-22944
  • Peer Reviewed
• [Journal Article] HIV-Tat targets Tip60 to impair the apoptotic cell response to genotoxic stresses. (2005)
  • Author(s): Col, E., Caron, C., Chable-Bessia, C., Legube, G., Gazzeri, S., Komatsu, Y., Yoshida, M., Benkirane, M., Trouche, D., Khochbin, S.
  • Journal Title: EMBO J. 24 Pages: 2634-2645
  • Peer Reviewed
• [Journal Article] Inhibition of protein synthesis and activation of stress-activated protein kinases by onnamide A and theopederin B, antitumor marine natural products. (2005)
  • Author(s): Lee, K. -H., Nishimura, S., Matsunaga, S., Fusetani, N., Horinouchi, S., Yoshida, M.
  • Journal Title: Cancer Sci. 96 Pages: 357-364
  • Peer Reviewed
• [Journal Article] T. -P. HDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptor. (2005)
  • Author(s): Kovacs, J.J., Murphy, P.J.M., Gaillard, S., Zhao, X., Wu, J. -T., Nicchitta, C.V., Yoshida, M., Toft, D.O., Pratt, W.B., Yao
  • Journal Title: Mol. Cell 18 Pages: 601-607
  • Peer Reviewed
• [Journal Article] Design and synthesis of phthalimide-type histone deacetylase inhibitors. (2005)
  • Author(s): Shinji, C., Nakamura, T., Maeda, S., Yoshida, M., Hashimoto, Y., Miyachi, H.
  • Journal Title: Bioorg Med Chem Lett. 15 Pages: 4427-4431
  • Peer Reviewed
• [Journal Article] Significance of HDAC6 regulation via estrogen signaling for cell motility and prognosis in estrogen receptor-positive breast cancer. (2005)
  • Author(s): Saji, S., Kawakami, M., Hayashi, S.I., Yoshida, N., Hirose, M., Horiguchi, S.I., Itoh, A., Funata, N., Schreiber, S.L., Yoshida, M., Toi, M.
  • Journal Title: Oncogene 24 Pages: 4531-4539
  • Peer Reviewed
• [Presentation] Forward and reverse proteomic approaches for functional analysis of non-nuclear sirtuins. FASEB (Federation of American Societies for Experimental Biology) Summer Research Conferences (2009)
  • Author(s): Minoru Yoshida.
  • Organizer: Histone Deacetylases and Reversible Acetylation in Signaling and Disease
  • Place of Presentation: Lucca, Italy.
  • Year and Date: 20090809-20090814
• [Presentation] 遺伝子発現とエピジェネティクスを制御する新たな分子標的の探索. 岩手医科大学 (2009)
  • Author(s): 吉田稔
  • Organizer: 化学療法基盤情報支援班共催シンポジウム「抗がん剤創薬の新たな展開」
  • Place of Presentation: 矢巾町
  • Year and Date: 2009-01-16
• [Presentation] Splicing factor SF3b as a novel target for cancer therapy. (2008)
  • Author(s): Minoru Yoshida.
  • Organizer: The 13th Japanese Foundation for Cancer Research International Symposium on Cancer Chemotherapy
  • Place of Presentation: Tokyo, Japan.
  • Year and Date: 20081203-20081204
• [Presentation] ケミカルジェネティクスによる抗がん剤分子標的の探索 (2008)
  • Author(s): 吉田稔
  • Organizer: 第55回日本臨床検査医学会学術集会
  • Place of Presentation: 名古屋
  • Year and Date: 20081127-20081130
• [Presentation] クロマチン機能を標的としたケミカルバイオロジー (2008)
  • Author(s): 吉田稔
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 20081028-20081030
• [Presentation] Chemical genetics for novel anticancer microbial products. (2008)
  • Author(s): Minoru Yoshida.
  • Organizer: The 4th Finland-Japan Meeting on Biotechnology
  • Place of Presentation: Sapporo, Japan.
  • Year and Date: 20081001-20081003
• [Presentation] Chemical genetics of a small molecule cell cycle inhibitor that inhibits pre-mRNA splicing. (2007)
  • Author(s): Minoru Yoshida.
  • Organizer: The 4th Takeda Science Foundation Symposium on Pharma Sciences on the Frontiers of Chemical Biology
  • Place of Presentation: Tokyo, Japan
  • Year and Date: 20071203-20071204
• [Presentation] Identification of a spliceosome sub-complex SF3b as a novel target for cancer therapy. (2007)
  • Author(s): 吉田稔
  • Organizer: 第66回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 20071003-20071005
• [Presentation] Extracellular signal- dependent protein lysine acetylation as a molecular modulator for cellular functions. FASEB (Federation of American Societies for Experimental Biology) (2007)
  • Author(s): Minoru Yoshida.
  • Organizer: Summer Research Conferences
  • Place of Presentation: Snowmass Village, USA.
  • Year and Date: 20070602-20070607
• [Book] Methods in Molecular Biology (Methods Mol. Biol. ) Vol. 577: Reverse chemical genetics methods and protocols. (2009)
  • Author(s): Akihisa Matsuyama, Minoru Yoshida.
  • Total Pages: 11-24
  • Publisher: Humana Press
• [Book] Totowa New Jersey. Histone Deacetylases: Transcriptional Regulation and Other Cellular Functions. (2006)
  • Author(s): Akihiro Ito, Norikazu Nishino, Minoru Yoshida.
  • Total Pages: 271-297
  • Publisher: Humana Press
• [Book] ケミカルバイオロジー・ケミカルゲノミクス (2005)
  • Author(s): 吉田稔
  • Total Pages: 191-207
  • Publisher: シュプリンガー・フェアラーク
• [Patent(Industrial Property Rights)] ヒストン脱アセチル化酵素阻害剤およびその製造方法 (2010)
  • Inventor(s): 吉田稔、西野憲和
  • Industrial Property Rights Holder: 理化学研究所
  • Industrial Property Number: 特許EP1640380
  • Acquisition Date: 2010-03-10
• [Patent(Industrial Property Rights)] ヒストン脱アセチル化酵素阻害剤およびその製造方法 (2010)
  • Inventor(s): 吉田稔、西野憲和
  • Industrial Property Rights Holder: 理化学研究所
  • Industrial Property Number: 特許US7662778
  • Acquisition Date: 2010-03-10
• [Patent(Industrial Property Rights)] ヒストン脱アセチル化酵素阻害活性を有する化合物とそれを有効成分とする医薬(ヒストン脱アセチル化酵素の阻害剤およびその製造方法) (2007)
  • Inventor(s): 西野憲和、吉田稔、中川純一
  • Industrial Property Rights Holder: 九州工業大学、理化学研究所、大正製薬株式会社
  • Industrial Property Number: 特許PCT/JP2007/064873
  • Filing Date: 2007-07-31
• [Patent(Industrial Property Rights)] ヒストン脱アセチル化酵素阻害活性を有する化合物とそれを有効成分とする医薬 (2006)
  • Inventor(s): 西野憲和、吉田稔、中川純一
  • Industrial Property Rights Holder: 九州工業大学、理化学研究所、大正製薬株式会社
  • Industrial Property Number: 特許特願2006-239901
  • Filing Date: 2006-09-05
• [Patent(Industrial Property Rights)] HDAC阻害活性を有する新規置換ヒドロキサム酸誘導体 (2005)
  • Inventor(s): 宮地弘幸、橋本祐一、進士千尋、吉田稔
  • Industrial Property Rights Holder: 東京大学、理化学研究所
  • Industrial Property Number: 特許特願2005-267767
  • Filing Date: 2005-09-15