Development of Novel Drug Discovery Technologies for Target Proteins with Elusive Molecular Basis

• Project/Area Number: 15H04654
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Drug development chemistry
• Research Institution: Kyoto University
• Principal Investigator: Fujii Nobutaka 京都大学, 薬学研究科, 名誉教授 (60109014)
• Co-Investigator(Kenkyū-buntansha): 大野 浩章 京都大学, 薬学研究科, 教授 (30322192)
• Co-Investigator(Renkei-kenkyūsha): NAKANISHI Isao 近畿大学, 薬学部, 教授 (10362576) ; OISHI Shinya 京都大学, 大学院薬学研究科, 准教授 (80381739)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2017: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2016: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2015: ¥9,360,000 (Direct Cost: ¥7,200,000、Indirect Cost: ¥2,160,000)
• Keywords: ペプチド / 複素環 / GPCR / ケモカイン / 創薬テンプレート / 合理的分子設計 / キナーゼ / 環状ペプチド

Outline of Final Research Achievements

Through the structure-activity relationship study of cyclic pentapeptide CXCR7 ligands, a number of potent and highly selective ligands were identified. The binding modes and structural requirements of some representative ligands were revealed by molecular modeling studies. Efficient synthetic approaches for alkaloid scaffolds were developed, which can be applicable to medicinal chemistry studies. Furthermore, several inhibitory molecules with unique biological and/or functional properties were identified against sphingosine kinases, CK2 kinases and NK3 receptor via the structure-activity relationship studies.

Research Products

• [Int'l Joint Research] モントリオール大学(カナダ)
• [Int'l Joint Research] モントリオール大学(カナダ)
• [Int'l Joint Research] フランス国立保健医学研究所(フランス)
• [Int'l Joint Research] モントリオール大学(カナダ)
• [Journal Article] Synthesis of Jaspine B Regioisomers through Palladium-Catalyzed Stereoselective Tetrahydrofuran Formation: Insight into the Ligand Recognition of Sphingosine Kinases (2018)
  • Author(s): Miyagawa, S. Inuki, M. Honda, S. Nakamura, I. Nakanishi, N. Fujii, S. Oishi, H. Ohno
  • Journal Title: Tetrahdron Volume: 74 Issue: 15 Pages: 1802-1809
  • DOI: 10.1016/j.tet.2018.02.042
  • Peer Reviewed
• [Journal Article] Head-to-Tail Macrocyclization of Cysteine-Free Peptides Using an o-Aminoanilide Linker (2018)
  • Author(s): T. Ohara, M. Kaneda, T. Saito, N. Fujii, H. Ohno, S. Oishi
  • Journal Title: Bioorg. Med. Chem. Lett. Volume: 28 Issue: 8 Pages: 1283-1286
  • DOI: 10.1016/j.bmcl.2018.03.027
  • Peer Reviewed
• [Journal Article] Structure-Activity Relationship Study of Cyclic Pentapeptide Ligands for Atypical Chemokine Receptor 3 (ACKR3) (2018)
  • Author(s): Sekiguchi Haruka、Kuroyanagi Tomoko、Rhainds David、Kobayashi Kazuya、Kobayashi Yuka、Ohno Hiroaki、Heveker Nikolaus、Akaji Kenichi、Fujii Nobutaka、Oishi Shinya
  • Journal Title: Journal of Medicinal Chemistry Volume: 61 Issue: 8 Pages: 3745-3751
  • DOI: 10.1021/acs.jmedchem.8b00336
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Total Synthesis of Dictyodendrins by the Gold-Catalyzed Cascade Cyclization of Conjugated Diynes with Pyrroles (2017)
  • Author(s): J. Matsuoka, Y. Matsuda, Y. Kawada, S. Oishi, H. Ohno
  • Journal Title: Angew. Chem. Int. Ed. Volume: 56 Issue: 26 Pages: 7444-7448
  • DOI: 10.1002/anie.201703279
  • Peer Reviewed
• [Journal Article] Identification of Selective Inhibitors of Sphingosine Kinases 1 and 2 through a Structure-Activity Relationship Study of 4-epi-Jaspine B (2017)
  • Author(s): H. Ohno, M. Honda, N. Hamada, J. Miyagaki, A. Iwata, K. Otsuki, T. Maruyama, S. Nakamura, I. Nakanishi, S. Inuki, N. Fujii, S. Oishi
  • Journal Title: Bioorg. Med. Chem. Volume: 25 Issue: 12 Pages: 3046-3052
  • DOI: 10.1016/j.bmc.2017.03.059
  • Peer Reviewed
• [Journal Article] Novel 3,4,7-Substituted Benzofuran Derivatives Having Binding Affinity to κ-Opioid Receptor (2016)
  • Author(s): D. Nishiyama, Y. Sakai, H. Sekiguchi, H. Chiba, R. Misu, S. Oishi, N. Fujii, H. Ohno
  • Journal Title: Chemical and Pharmaceutical Bulletin Volume: 64 Issue: 7 Pages: 996-1003
  • DOI: 10.1248/cpb.c16-00302
  • NAID: 130005160050
  • ISSN: 0009-2363, 1347-5223
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Development of novel NK3 receptor antagonists with reduced environmental impact (2016)
  • Author(s): Yamamoto Koki、Okazaki Shiho、Ohno Hiroaki、Matsuda Fuko、Ohkura Satoshi、Maeda Kei-ichiro、Fujii Nobutaka、Oishi Shinya
  • Journal Title: Bioorganic & Medicinal Chemistry Volume: 24 Issue: 16 Pages: 3494-3500
  • DOI: 10.1016/j.bmc.2016.05.054
  • Peer Reviewed
• [Journal Article] Total Synthesis of (+)-Conolidine by the Gold(I)-Catalyzed Cascade Cyclization of a Conjugated Enyne (2016)
  • Author(s): S. Naoe, Y. Yoshida, S. Oishi, N. Fujii, H. Ohno
  • Journal Title: J. Org. Chem. Volume: 81 Issue: 13 Pages: 5690-5698
  • DOI: 10.1021/acs.joc.6b00720
  • NAID: 120006634624
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] CXCL12/CXCR4 pathway is activated by oncogenic JAK2 in a PI3K-dependent manner (2016)
  • Author(s): Abdelouahab Hadjer、Zhang Yanyan、Wittner Monika、Oishi Shinya、Fujii Nobutaka、Besancenot Rodolphe、Plo Isabelle、Ribrag Vincent、Solary Eric、Vainchenker William、Barosi Giovanni、Louache Fawzia
  • Journal Title: Oncotarget Volume: 8 Issue: 33 Pages: 54082-54095
  • DOI: 10.18632/oncotarget.10789
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A Novel Peptide Derived from the Fusion Protein Heptad Repeat Inhibits Replication of Subacute Sclerosing Panencephalitis Virus In Vitro and In Vivo. (2016)
  • Author(s): Watanabe M, Hashimoto K, Abe Y, Kodama EN, Nabika R, Oishi S, Ohara S, Sato M,Kawasaki Y, Fujii N, Hosoya M.
  • Journal Title: PLoS One. Volume: 11 Issue: 9 Pages: e0162823-e0162823
  • DOI: 10.1371/journal.pone.0162823
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Enhanced antibody-mediated neutralization of HIV-1 variants that are resistant to fusion inhibitors (2016)
  • Author(s): Alam, M., Kuwata, T., Shimura, K., Yokoyama, M., Ramirez Valdez, K. P., Tanaka, K., Maruta, Y., Oishi, S., Fujii, N., Sato, H., Matsuoka M. and Matsushita S.
  • Journal Title: Retrovirology Volume: 13 Issue: 1 Pages: 70-70
  • DOI: 10.1186/s12977-016-0304-7
  • NAID: 120005973385
  • Peer Reviewed / Open Access
• [Journal Article] Structure-Activity Relationship Study of 4-(Thiazol-5-yl)benzoic Acid Derivatives as Potent Protein Kinase CK2 Inhibitors (2016)
  • Author(s): H. Ohno, D. Minamiguchi, S. Nakamura, K. Shu, S. Okazaki, M. Honda, R. Misu, H. Moriwaki, S. Nakanishi, S. Oishi, T. Kinoshita, I. Nakanishi, N. Fujii
  • Journal Title: Bioorg. Med. Chem. Volume: 24 Issue: 5 Pages: 1136-1141
  • DOI: 10.1016/j.bmc.2016.01.043
  • Peer Reviewed
• [Journal Article] Formal Total Synthesis of (±)-Strictamine Based on a Gold-Catalyzed Cyclization (2016)
  • Author(s): D. Nishiyama, A. Ohara, H. Chiba, H. Kumagai, S. Oishi, N. Fujii, H. Ohno
  • Journal Title: Org. Lett. Volume: 18 Issue: 7 Pages: 1670-1673
  • DOI: 10.1021/acs.orglett.6b00536
  • NAID: 120006634625
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Screening of a virtual mirror-image library of natural products (2016)
  • Author(s): T. Noguchi, S. Oishi, K. Honda, Y. Kondoh, T. Saito, H. Ohno, H. Osada, N. Fujii
  • Journal Title: Chem. Comm. Volume: 52 Issue: 49 Pages: 7653-7656
  • DOI: 10.1039/c6cc03114e
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Synthesis of Fused Carbazoles by Gold-Catalyzed Tricyclization of Conjugated Diynes via Rearrangement of an N-Propargyl Group (2015)
  • Author(s): M. Taguchi, Y. Tokimizu, S. Oishi, N. Fujii, H. Ohno
  • Journal Title: Org. Lett. Volume: 17 Issue: 24 Pages: 6250-6253
  • DOI: 10.1021/acs.orglett.5b03254
  • NAID: 120006634626
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Pd触媒を用いたTHF環構築によるJaspine B 位置異性体の合成研究 (2018)
  • Author(s): 宮川貴吏、本田真歩、中村真也、仲西功、井貫晋輔、大石真也、大野浩章
  • Organizer: 日本薬学会第138年会
• [Presentation] Dictyodendrin類の多様性志向型全合成 (2017)
  • Author(s): 松岡純平、松田優佳、川田惟樹、大石真也、大野浩章
  • Organizer: 第15回次世代を担う有機化学シンポジウム
• [Presentation] Dbzリンカーを用いた環状ペプチドの合成研究 (2017)
  • Author(s): 大原拓己、金田雅仁、齋藤知、大野浩章、大石真也
  • Organizer: 第49回若手ペプチド夏の勉強会
• [Presentation] Total synthesis of dictyodendrins by the gold-catalyzed intermolecular cascade cyclization of conjugated diynes with pyrroles (2017)
  • Author(s): Junpei Matsuoka, Yuka Matsuda, Yuiki Kawada, Shinya Oishi, Hiroaki Ohno
  • Organizer: 254th ACS National Meeting
  • Int'l Joint Research
• [Presentation] Development of novel NK3 receptor antagonists with reduced environmental impact (2017)
  • Author(s): Koki Yamamoto, Hiroaki Ohno, Nobutaka Fujii, Shinya Oishi
  • Organizer: 254th ACS National Meeting
  • Int'l Joint Research
• [Presentation] 4-epi-Jaspine B位置異性体の合成と構造活性相関研究 (2017)
  • Author(s): 宮川貴吏、本田真歩、小林由佳、中村真也、仲西功、藤井信孝、井貫晋輔、大石真也、大野浩章
  • Organizer: 第34回有機合成化学セミナー
• [Presentation] 金触媒を用いた分子内連続環化反応を基盤としたAspidophylline Aの全合成研究 (2017)
  • Author(s): 奥村怜司、大原礼子、熊谷洋、大石真也、大野浩章
  • Organizer: 第59回天然有機化合物討論会
• [Presentation] CXCR7受容体選択的リガンドの構造活性相関研究 (2017)
  • Author(s): 関口遼、黒柳友子、小林由佳、小林数也、赤路健一、藤井信孝、大野浩章、大石真也
  • Organizer: 第35回メディシナルケミストリーシンポジウム
• [Presentation] Dictyodendrin類の網羅的全合成と誘導体の活性評価 (2017)
  • Author(s): 松岡純平、松田優佳、川田惟樹、大石真也、大野浩章
  • Organizer: 第43回反応と合成の進歩シンポジウム
• [Presentation] Development of peptide macrocyclization protocol utilizing o-aminoanilide linker for flow chemistry (2017)
  • Author(s): Takumi Ohara, Masato Kaneda, Tomo Saito, Hiroaki Ohno, Shinya Oishi
  • Organizer: 第54回ペプチド討論会
• [Presentation] ケモカイン受容体CXCR7選択的リガンドの構造最適化研究 (2017)
  • Author(s): 関口遼、黒柳友子、小林由佳、藤井信孝、大野浩章、大石真也
  • Organizer: 日本薬学会第137回年会
• [Presentation] Dictyodendrin類の全合成研究 (2017)
  • Author(s): 松岡純平、松田優佳、川田惟樹、大石真也、大野浩章
  • Organizer: 日本薬学会第137回年会
• [Presentation] 長時間作用型PEG化NK3受容体作動薬の創製 (2016)
  • Author(s): 桑井真司、大石真也、三須良介、大野浩章、山村崇、若林嘉浩、岡村裕昭、藤井信孝
  • Organizer: 日本薬学会第136回年会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-03-26
• [Presentation] Facile access to the mirror-image library of chiral natural product derivatives: identification of MDM2-p53 interaction inhibitor (2016)
  • Author(s): Taro Noguchi, Shinya Oishi, Kaori Honda, Yasumitsu Kondoh, Tamio Saito, Hiroaki Ohno, Hiroyuki Osada, Nobutaka Fujii
  • Organizer: 第8回武田振興財団薬科学シンポジウム
  • Place of Presentation: 武田研修センター（大阪府吹田市）
  • Year and Date: 2016-01-21
• [Presentation] Total synthesis of a novel cytotoxic depsipeptide from Okinawan marine cyanobacteria (2016)
  • Author(s): Masato Kaneda, Shinya Oishi, Kosuke Sueyoshi, Toshiaki Teruya, Hiroaki Ohno and Nobutaka Fujii
  • Organizer: 第8回武田振興財団薬科学シンポジウム
  • Place of Presentation: 武田研修センター（大阪府吹田市）
  • Year and Date: 2016-01-21
• [Presentation] Development of Novel CXCR7 Ligands: Selectivity Switch from CXCR4 Antagonists with Cyclic Pentapeptide Scaffold (2016)
  • Author(s): Tomoko Kuroyanagi, Shinya Oishi, Tatsuhiko Kubo, Yuka Kobayashi, Haruka Sekiguchi, Ryosuke Misu, Hiroaki Ohno, Nicolas Montpas, Nikolaus Heveker, Nobutaka Fujii
  • Organizer: 第8回武田振興財団薬科学シンポジウム
  • Place of Presentation: 武田研修センター（大阪府吹田市）
  • Year and Date: 2016-01-21
• [Presentation] ケモカイン受容体CXCR7 選択的リガンドの構造最適化研究 (2016)
  • Author(s): 関口遼、大石真也、黒柳友子、小林由佳、大野浩章、藤井信孝
  • Organizer: 日本ケミカルバイオロジー学会 第11回年会
• [Presentation] Design of iron-chelating cyclic peptides (2016)
  • Author(s): Yuka Kobayashi, Shinya Oishi, Hiroaki Ohno, Nobutaka Fujii
  • Organizer: 8th International Peptide Symposium
  • Int'l Joint Research
• [Presentation] 金触媒を用いたアスピドスペルマ型アルカロイド骨格構築法の開発--Aspidosprmidineの合成研究-- (2016)
  • Author(s): 熊谷洋、大石真也、大野浩章
  • Organizer: 第66回日本薬学会近畿支部総会・大会
• [Presentation] Design of Fe(II)-chelaing cyclic hexapeptide with bidentate pyridinyl-triazlole groups (2016)
  • Author(s): Yuka Kobayashi, Shinya Oishi, Hiroaki Ohno, Nobutaka Fujii
  • Organizer: 第53回ペプチド討論会
• [Presentation] Strictamineの不斉形式全合成 (2016)
  • Author(s): 熊谷洋、西山大亮、大石真也、藤井信孝、大野浩章
  • Organizer: 第42回反応と合成の進歩シンポジウム
• [Presentation] Gold-catalyzed construction of tetracyclic skeleton for aspidosperma alkaloid synthesis: Synthetic study on (±)-aspidospermidine (2016)
  • Author(s): Hiroshi Kumagai, Shinya Oishi, Hiroaki Ohno
  • Organizer: ISONIS-10
  • Int'l Joint Research
• [Presentation] Strictamineの全合成研究 (2016)
  • Author(s): 西山大亮、大原礼子、熊谷洋、千葉浩亮、藤井信孝、大石真也、大野浩章
  • Organizer: 第34回メディシナルケミストリーシンポジウム
• [Presentation] Gold-Catalyzed Cascade Cyclizations of Alkynes for Construction of Nitrogen Heterocycles (2015)
  • Author(s): Hiroaki Ohno
  • Organizer: Pacifichem 2015
  • Place of Presentation: Hilton Hawaiian Village（アメリカ、ホノルル）
  • Year and Date: 2015-12-15
  • Int'l Joint Research / Invited
• [Presentation] Novel screening approach for drug discovery from virtual mirror-image library of natural products (2015)
  • Author(s): Taro Noguchi, Shinya Oishi, Kaori Honda, Yasumitsu Kondoh, Tamio Saito, Hiroaki Ohno, Hiroyuki Osada, Nobutaka Fujii
  • Organizer: Pacifichem 2015
  • Place of Presentation: Hilton Hawaiian Village（アメリカ、ホノルル）
  • Year and Date: 2015-12-15
  • Int'l Joint Research
• [Presentation] PEG修飾による長時間作用型NK3受容体作動薬の創製 (2015)
  • Author(s): 桑井真司、 大石真也、三須良介、岡崎志穂、山本昂輝、大野浩章、山村崇、若林嘉浩、岡村裕昭、藤井信孝
  • Organizer: 第33回メディシナルケミストリーシンポジウム
  • Place of Presentation: 幕張国際研修センター（千葉県幕張市）
  • Year and Date: 2015-11-25
• [Presentation] ケモカイン受容体CXCR7選択的リガンドの構造最適化研究 (2015)
  • Author(s): 黒柳友子，大石真也，小林由佳，関口遼，三須良介，大野浩章，Montpas Nicolas，Heveker Nikolaus，藤井信孝
  • Organizer: 第33回メディシナルケミストリーシンポジウム
  • Place of Presentation: 幕張国際研修センター（千葉県幕張市）
  • Year and Date: 2015-11-25
• [Presentation] 環境調和型NK3受容体拮抗剤の創製研究 (2015)
  • Author(s): 山本昂輝、 大石真也、大野浩章、藤井信孝
  • Organizer: 第33回メディシナルケミストリーシンポジウム
  • Place of Presentation: 幕張国際研修センター（千葉県幕張市）
  • Year and Date: 2015-11-25
• [Presentation] 共役ジインとピロールを用いた金触媒[4+2]型インドール合成と縮環骨格構築への展開 (2015)
  • Author(s): 松田優佳、直江紗織、大石真也、藤井信孝、大野浩章
  • Organizer: 第45回複素環化学討論会
  • Place of Presentation: 早稲田大学（東京都新宿区）
  • Year and Date: 2015-11-19
• [Presentation] プロパルギル転位を伴う共役ジインの金触媒三連続環化反応を用いたカルバゾールの合成 (2015)
  • Author(s): 田口将光、時水勇輔、大石真也、藤井信孝、大野浩章
  • Organizer: 第45回複素環化学討論会
  • Place of Presentation: 早稲田大学（東京都新宿区）
  • Year and Date: 2015-11-19
• [Presentation] Identification of a novel MDM2-p53 inhibitor using mirror-image-screening technology for chiral natural products (2015)
  • Author(s): Taro Noguchi, Shinya Oishi, Kaori Honda, Yasumitsu Kondoh, Tamio Saito, Hiroaki Ohno, Hiroyuki Osada, Nobutaka Fujii
  • Organizer: SKO symposium
  • Place of Presentation: New Drug Development Center, Seoul University（韓国、ソウル）
  • Year and Date: 2015-11-17
  • Int'l Joint Research
• [Presentation] Development of Novel CXCR7 Ligands by Selectivity Switch from CXCR4 Antagonists with a Cyclic Pentapeptide Scaffold (2015)
  • Author(s): Shinya Oishi, Tomoko Kuroyanagi, Tatsuhiko Kubo, Nicolas Montpas, Yasushi Yoshikawa, Ryosuke Misu, Yuka Kobayashi, Hiroaki Ohno, Nikolaus Heveker, Toshio Furuya, and Nobutaka Fujii
  • Organizer: AIMECS2015
  • Place of Presentation: Jeju international convention center（韓国、済州島）
  • Year and Date: 2015-10-18
  • Int'l Joint Research / Invited
• [Presentation] 天然物とその誘導体の鏡像体化合物群の活用を目指した新規スクリーニング法の開発 (2015)
  • Author(s): 野口太朗、大石真也、本田香織、近藤恭光、斎藤臣雄、大野浩章、長田裕之、藤井信孝
  • Organizer: 日本ケミカルバイオロジー学会 第10回年会
  • Place of Presentation: 東北大学川内キャンパス（宮城県仙台市）
  • Year and Date: 2015-06-10
• [Presentation] アルキンの活性化を基盤とする連続反応の開発と応用 (2015)
  • Author(s): 大野浩章
  • Organizer: 日本薬学会東海支部特別講演会
  • Place of Presentation: 岐阜薬科大学（岐阜県岐阜市）
  • Invited
• [Presentation] ケモカイン受容体CXCR7選択的リガンドの構造最適化研究 (2015)
  • Author(s): 黒柳友子，大石真也，久保達彦，三須良介，小林由佳，大野浩章，Montpas Nicolas，Heveker Nikolaus，吉川寧，古谷利夫，藤井信孝
  • Organizer: 第65回日本薬学会 近畿支部総会・大会
  • Place of Presentation: 大阪大谷大学（大阪府羽曳野市）
• [Presentation] アルキンの活性化を基盤とする複素環骨格構築反応の開発と応用 (2015)
  • Author(s): 大野浩章
  • Organizer: 京大有機金属化学若手勉強会
  • Place of Presentation: 京都大学薬学研究科（京都府京都市）
  • Invited
• [Presentation] 金触媒によるアルキンの活性化を用いた骨格構築反応の開発と応用 (2015)
  • Author(s): 大野浩章
  • Organizer: 名城大学特別講演会
  • Place of Presentation: 名城大学薬学部（愛知県名古屋市）
  • Invited
• [Remarks] 研究室ホームページ
  • URL: http://www.pharm.kyoto-u.ac.jp//seizo/