Development of a therapeutic drug for bone-related diseases based on chemical genetics

• Project/Area Number: 26750373
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Chemical biology
• Research Institution: Juntendo University (2015); Keio University (2014)
• Principal Investigator: Sasazawa Yukiko 順天堂大学, 医学部, 特任研究員 (20594922)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2014: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: ケミカルジェネティクス / 骨粗鬆症 / 破骨細胞 / 破骨細胞分化 / ケミカルバイオロジー

Outline of Final Research Achievements

In order to identify a new therapeutic drug for bone-related diseases, we screened for small-molecules that inhibit osteoclast differentiation. We found that a novel compound, SUKU-1, suppressed RANKL-induced osteoclastogenesis. We also synthesized 38 derivatives of SUKU-1 and identified SUKU-33 as a most potent inhibitor. We found SUKU-33 suppressed RANKL-induced expression of osteoclast-related genes. By measuring the uptake of [3H]-uridine, we found that SUKU-33 inhibited transport of nucleoside via both equilibrative nucleoside transporters and concentrative nucleoside transporters. These results suggest that SUKU-33 inhibits osteoclastogenesis by suppressing nucleoside transporters.

Research Products

• [Journal Article] Identification of seco-clavilactone B as a novel small-molecule actin polymerization inhibitor. (2016)
  • Author(s): Miyazaki, S., Sasazawa, Y., Mogi, T., Suzuki, T., Yoshida, K., Dohmae, N., Takao, K. & Simizu, S.
  • Journal Title: FEBS Lett. Volume: 590 Issue: 8 Pages: 1163-73
  • DOI: 10.1002/1873-3468.12154
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Identification of a novel compound that inhibits osteoclastogenesis by suppressing nucleoside transporters. (2016)
  • Author(s): S. Katsuyama, K. Sugino, Y. Sasazawa, Y. Nakano, H. Aono, K. Morishita, M. Kawatani, K. Umezawa, H. Osada and S. Simizu
  • Journal Title: FEBS Letters Volume: 590 Issue: 8 Pages: 1152-1162
  • DOI: 10.1002/1873-3468.12146
  • Peer Reviewed
• [Journal Article] C-mannosylation of thrombopoietin receptor (c-Mpl) regulates thrombopoietin-dependent JAK-STAT signaling. (2015)
  • Author(s): Sasazawa, Y., Sato, N., Suzuki, T., Dohmae, N. & Simizu, S.
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 468 Issue: 1-2 Pages: 262-268
  • DOI: 10.1016/j.bbrc.2015.10.116
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Identification of a Molecular Target of Kurahyne, an Apoptosis-inducing Lipopeptide from Marine Cyanobacterial Assemblages (2015)
  • Author(s): Arihiro Iwasaki, Osamu Ohno, Shun Katsuyama, Maho Morita, Yukiko Sasazawa, Shingo Dan, Siro Simizu, Takao Yamori, Kiyotake Suenaga
  • Journal Title: Bioorganic & Medicinal Chemistry Letters Volume: 25 Issue: 22 Pages: 5295-5298
  • DOI: 10.1016/j.bmcl.2015.09.044
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Pirin regulates the epithelial to mesenchymal transition independently of Bcl3-Slug signaling. (2015)
  • Author(s): Komai, K., Niwa, Y., Sasazawa, Y. & Simizu, S.
  • Journal Title: FEBS Lett. Volume: 589 Issue: 6 Pages: 738-743
  • DOI: 10.1016/j.febslet.2015.01.040
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Conophylline Protects Cells in Cellular Models of Neurodegenerative Diseases by Inducing Mammalian Target of Rapamycin (mTOR)-independent Autophagy (2015)
  • Author(s): Sasazawa Y, Sato N, Umezawa K, Simizu S.
  • Journal Title: J. Biol. Chem. Volume: 290 Issue: 10 Pages: 6168-6178
  • DOI: 10.1074/jbc.m114.606293
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] SMK-17, a MEK1/2-specific inhibitor, selectively induces apoptosis in β-catenin-mutated tumors. (2015)
  • Author(s): Kiga M, Nakayama A, Shikata Y, Sasazawa Y, Murakami R, Nakanishi T, Tashiro E, Imoto M.
  • Journal Title: Scientific Report Volume: 5 Issue: 1 Pages: 8155-8155
  • DOI: 10.1038/srep08155
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] N-Glycosylation of extracellular matrix protein 1 (ECM1) regulates its secretion, which is unrelated to lipoid proteinosis (2015)
  • Author(s): Uematsu S, Goto Y, Suzuki T, Sasazawa Y, Dohmae N, Simizu S.
  • Journal Title: FEBS Open Bio Volume: 4 Issue: 1 Pages: 879-885
  • DOI: 10.1016/j.fob.2014.10.004
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] A novel osteoclast inhibitor targeting nucleoside transporters. (2016)
  • Author(s): Katsuyama, K., Sugino, K., Sasazawa, Y., Nakano, Y., Aono, A., Kawatani, M., Osada, H. & Simizu. S.
  • Organizer: The 10th Korea-Japan Chemical Biology Symposium
  • Place of Presentation: パシフィックホテル沖縄 (沖縄県那覇市）
  • Year and Date: 2016-01-18
  • Int'l Joint Research
• [Presentation] パーキンソン病モデル細胞におけるメタボローム解析 (2015)
  • Author(s): 笹澤有紀子、王子悠、斉木臣二、服部信孝
  • Organizer: 第9回オートファジー研究会
  • Place of Presentation: 淡路夢舞台国際会議場 (兵庫県淡路市)
  • Year and Date: 2015-11-15
• [Presentation] Pirin regulates protein level of oncogenic transcription factor Ets1. (2015)
  • Author(s): Shimizu, E., Komai, K., Sasazawa,Y. & Simizu,S.
  • Organizer: 第74回 日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場 (愛知県名古屋市)
  • Year and Date: 2015-10-08
• [Presentation] The Biological Activity of Clavilactones and Their Analogues. (2015)
  • Author(s): Miyazaki, S., Sasazawa, Y., Yoshida, K., Takao,K. & Simizu, S.
  • Organizer: 第74回 日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場 (愛知県名古屋市)
  • Year and Date: 2015-10-08
• [Presentation] 小分子化合物SUK-14による破骨細胞分化抑制メカニズムの解析 (2015)
  • Author(s): 勝山俊、杉野公美、笹澤有紀子、川谷誠、長田裕之、清水史郎
  • Organizer: 日本農芸化学会2015年度関東支部大会
  • Place of Presentation: お茶の水女子大学 (東京都文京区)
  • Year and Date: 2015-09-26
• [Presentation] R-spondin3におけるC型糖修飾の同定とその役割 (2015)
  • Author(s): 加藤慎大郎、藤原未帆、丹羽祐貴、鈴木健裕、土屋みゆ、笹澤有紀子、堂前直、清水史郎
  • Organizer: GlycoTOKYO 2015
  • Place of Presentation: 慶應義塾大学 (神奈川県横浜市)
  • Year and Date: 2015-09-24
• [Presentation] Glycosylation of c-MPL affects JAK/STAT signaling pathway. (2015)
  • Author(s): Sato, N., Sasazawa, Y., Suzuki, T., Dohmae, N. & Simizu, S.
  • Organizer: GLYCO 23 XXIII International Symposium on Glycoconjugates
  • Place of Presentation: Split, Croatia
  • Year and Date: 2015-09-15
  • Int'l Joint Research
• [Presentation] Glycosylation of granulocyte colony-stimulating factor receptor. (2015)
  • Author(s): Otani, K., Sato, N., Suzuki, T., Niwa, Y., Sasazawa, Y., Dohmae, N. & Simizu, S.
  • Organizer: GLYCO 23 XXIII International Symposium on Glycoconjugates
  • Place of Presentation: Split, Croatia
  • Year and Date: 2015-09-15
  • Int'l Joint Research
• [Presentation] Lipoprotein lipase is glycosylated at Trp417. (2015)
  • Author(s): Okamoto, S., Uematsu, S., Suzuki, T., Niwa, Y., Sasazawa, Y., Dohmae, N. & Simizu, S.
  • Organizer: GLYCO 23 XXIII International Symposium on Glycoconjugates
  • Place of Presentation: Split, Croatia
  • Year and Date: 2015-09-15
  • Int'l Joint Research
• [Presentation] Glycosylation of R-spondin3 promotes its secretion and activates WNT/β-catenin signaling pathway. (2015)
  • Author(s): Simizu, S., Fujiwara, M., Niwa, Y., Suzuki T., Sasazawa, Y. & Dohmae, N.
  • Organizer: GLYCO 23 XXIII International Symposium on Glycoconjugates
  • Place of Presentation: Split, Croatia
  • Year and Date: 2015-09-15
  • Int'l Joint Research
• [Presentation] The role of C-mannosylation on c-mpl. (2015)
  • Author(s): Sato, N., Sasazawa, Y., Suzuki, T., Dohmae, N. & Simizu, S.
  • Organizer: 第34回日本糖質学会年会
  • Place of Presentation: 東京大学 (東京都文京区)
  • Year and Date: 2015-07-31
• [Presentation] C-mannosylation of granulocyte colony-stimulating factor receptor. (2015)
  • Author(s): Otani, K., Sato, N., Suzuki, T., Niwa, Y., Sasazawa, Y., Dohmae, N. & Simizu, S.
  • Organizer: 第34回日本糖質学会年会
  • Place of Presentation: 東京大学 (東京都文京区)
  • Year and Date: 2015-07-31
• [Presentation] Trp417 of lipoprotein lipase is glycosylated. (2015)
  • Author(s): Okamoto, S., Uematsu, S., Suzuki, T., Niwa, Y., Sasazawa,Y., Dohmae, N. & Simizu, S.
  • Organizer: 第34回日本糖質学会年会
  • Place of Presentation: 東京大学 (東京都文京区)
  • Year and Date: 2015-07-31
• [Presentation] Conophyllineによるオートファジー誘導と標的タンパク質の同定 (2015)
  • Author(s): 松木葵、笹澤有紀子、梅澤一夫、清水史郎
  • Organizer: 第19回学術集会 日本がん分子標的治療学会
  • Place of Presentation: 松山全日空ホテル (愛媛県松山市)
  • Year and Date: 2015-06-10
• [Presentation] MEK1/2選択的阻害剤SMK-17によるβ-catenin変異癌特異的アポトーシス誘導活性 (2015)
  • Author(s): 木我 真基、笹澤 有紀子、田代 悦、井本 正哉
  • Organizer: 第19回学術集会 日本がん分子標的治療学会
  • Place of Presentation: 松山全日空ホテル (愛媛県松山市)
  • Year and Date: 2015-06-10
• [Presentation] クラビラクトン類縁体の合成 (2015)
  • Author(s): 茂木 拓馬、吉田 圭佑、高尾 賢一、宮嵜 奏、笹澤 有紀子、清水 史郎
  • Organizer: 日本化学会第９５春季年会
  • Place of Presentation: 日本大学、千葉
  • Year and Date: 2015-03-26 – 2015-03-29
• [Presentation] Pirin downregulates E-cadherin gene expression and contributes to EMT. (2014)
  • Author(s): Komai, K., Niwa, Y., Sasazawa, Y. & Simizu, S.
  • Organizer: EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics
  • Place of Presentation: Barcelona, Spain
  • Year and Date: 2014-11-18 – 2014-11-21
• [Presentation] MEK1/2 specific inhibitor, SMK-17 selectively induces apoptosis in β-catenin mutated tumors. (2014)
  • Author(s): Kiga, M., Nakayama, A., Sasazawa, Y., Shikata, H., Ikeda, H., Tashiro, E. & Imoto, M.
  • Organizer: EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics
  • Place of Presentation: Barcelona, Spain
  • Year and Date: 2014-11-18 – 2014-11-21
• [Presentation] MEK1/2 specific inhibitor, SMK-17 selectively induces apoptosis in β-catenin mutated tumors. (2014)
  • Author(s): Kiga, M., Nakayama, A., Sasazawa, Y., Shikata, Y., Ikeda, H., Murakami, R., Nakanishi, T., Tashiro, E. & Imoto, M.
  • Organizer: 第73回 日本癌学会学術総会
  • Place of Presentation: Pacifico Yokohama, 横浜
  • Year and Date: 2014-09-27
• [Presentation] Secretion of Extracellular matrix protein 1 is regulated by N-glycosylation. (2014)
  • Author(s): Uematsu, S., Goto, Y., Sasazawa, Y. & Simizu, S.
  • Organizer: 第73回 日本癌学会学術総会
  • Place of Presentation: Pacifico Yokohama, 横浜
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Pirin regulates EMT by downregulating E-cadherin gene expression (2014)
  • Author(s): Komai, K., Niwa, Y., Sasazawa, Y. & Simizu, S.
  • Organizer: 第73回 日本癌学会学術総会
  • Place of Presentation: Pacifico Yokohama, 横浜
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] N-linked glycan which attached Asn354 regulate secretion of Extracellular matrix protein 1. (2014)
  • Author(s): Uematsu, S., Goto, Y., Suzuki, T., Sasazawa, Y., Dohmae, N. & Simizu, S.
  • Organizer: 15th International Biennial Congress of the Metastasis Research Society
  • Place of Presentation: Heidelberg, Germany
  • Year and Date: 2014-06-28 – 2014-07-01
• [Presentation] 破骨細胞分化阻害剤の作用機構解析 (2014)
  • Author(s): 笹澤有紀子、森下佳典、杉野公美、川谷誠、長田裕之、清水史郎
  • Organizer: 日本ケミカルバイオロジー学会第9回年会
  • Place of Presentation: 大阪大学、大阪
  • Year and Date: 2014-06-11 – 2014-06-13
• [Presentation] Conophyllineの抗ハンチントン病作用 (2014)
  • Author(s): 佐藤夏実、笹澤有紀子、梅澤一夫、清水史郎
  • Organizer: 日本ケミカルバイオロジー学会第9回年会
  • Place of Presentation: 大阪大学、大阪
  • Year and Date: 2014-06-11 – 2014-06-13