Development and application of novel chemical compounds to materialize the cancer theranostics

• Project/Area Number: 17K19670
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Research Field: General internal medicine and related fields
• Research Institution: Kyoto Pharmaceutical University
• Principal Investigator: Yasui Hiroyuki 京都薬科大学, 薬学部, 教授 (20278443)
• Co-Investigator(Kenkyū-buntansha): 木村 寛之 京都薬科大学, 薬学部, 准教授 (50437240) ; 有光 健治 京都薬科大学, 薬学部, 助教 (50707693) ; 戸崎 充男 京都大学, 環境安全保健機構, 准教授 (70207570) ; 河嶋 秀和 京都薬科大学, 薬学部, 准教授 (70359438) ; 中田 晋 京都薬科大学, 薬学部, 准教授 (80590695)
• Project Period (FY): 2017-06-30 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2018: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000); Fiscal Year 2017: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
• Keywords: がんTheranostics / フレキシブルTheranosticsプローブ / EGFR / EphA2 / PET/SPECTイメージング / EGFRvIII / Fzd3 / トランスポゾンシステムを用いたマウスモデル / 分子イメージング / がんの早期発見 / 画像診断法・治療法

Outline of Final Research Achievements

We have succeeded to design and synthesize several kinds of low molecular-weight organic RI-unlabeled compounds as potential candidates of imaging probes and therapeutic ligands targeted for the receptors such as EGFR,FGFR, and EphA2 as one of the tyrosine kinase type-receptor. Especially, the research and development of compound A as an imaging probe targeted for EGFR were most proceeded among this project, where the PET/CT imaging with F-18-labeled compound A indicated the faster hepatic metabolism and gradual distribution in the bones of brain skull and whole-body. If we use compound A for diagnosis of lung cancer, its distribution and accumulation in normal lung tissues will lead to the false positive diagnosis by the higher background levels and unclear contrasts. Then, we decided that the optimum time points for PET/CT imaging of lung cancer would be 120 min after i.v. injection of compound A. In conclusion, we have planned to carry out a patent application of compound A.

Academic Significance and Societal Importance of the Research Achievements

がん治療を目的とした新規化合物の開発については、腫瘍細胞に対する増殖抑制効果や細胞死誘導効果をインビトロ実験系により解析を進める必要や、薬理効果をインビボ実験系で評価する検討も必要ではあるが、最優先課題であった、がんTheranosticプローブとして有望なリード化合物を以下の様に創製することに成功した。
１）EGFRを標的とした低分子化合物A（肺がんのPET撮像に有効）、２）EGFRを標的としたTheranosticプローブであるモノクローナル抗体-キレート化合物（In-111, Y-90によるRI標識が可能）、３）EphA2を標的とした新規の低分子化合物B（乳がんのPET撮像に有効）。

Research Products

• [Journal Article] Structure?activity relationships of succinimidyl-Cys-C(O)-Glu derivatives with different near-infrared fluorophores as optical imaging probes for prostate-specific membrane antigen (2018)
  • Author(s): Matsuoka Daiko、Watanabe Hiroyuki、Shimizu Yoichi、Kimura Hiroyuki、Yagi Yusuke、Kawai Ryoko、Ono Masahiro、Saji Hideo
  • Journal Title: Bioorganic & Medicinal Chemistry Volume: 26 Issue: 9 Pages: 2291-2301
  • DOI: 10.1016/j.bmc.2018.03.015
  • Peer Reviewed
• [Journal Article] PET probe detecting non-small cell lung cancer susceptible to epidermal growth factor receptor tyrosine kinase inhibitor therapy (2018)
  • Author(s): Akira Makino , Anna Miyazaki , Ayaka Tomoike , Hiroyuki Kimura , Kenji Arimitsu , Masahiko Hirata , Yoshiro Ohmomo , Ryuichi Nishii , Hidehiko Okazawa , Yasushi Kiyono , Masahiro Ono , Hideo Saji
  • Journal Title: Bioorganic & Medical Chemistry Volume: 26 Issue: 8 Pages: 1609-1613
  • DOI: 10.1016/j.bmc.2018.02.007
  • Peer Reviewed
• [Journal Article] Development of a carboplatin derivative conjugated with a collagen-like triple-helical peptide (2018)
  • Author(s): Masuda Ryo、Hayashi Risa、Nose Hiroshi、Taguchi Akihiro、Hayashi Yoshio、Yasui Hiroyuki、Koide Takaki
  • Journal Title: Future Medicinal Chemistry Volume: 10 Issue: 6 Pages: 619-629
  • DOI: 10.4155/fmc-2017-0183
  • Peer Reviewed
• [Journal Article] Evaluation of 18F-labeled exendin(9-39) derivatives targeting glucagon-like peptide-1 receptor for pancreatic β-cell imaging. (2018)
  • Author(s): Kimura H, Ogawa Y, Fujimoto H, Mukai E, Kawashima H, Arimitsu K, Toyoda K, Fujita N, Yagi Y, Hamamatsu K, Murakami T, Murakami A, Ono M, Nakamoto Y, Togashi K, Inagaki N, Saji H.
  • Journal Title: Bioorganic & Medicinal Chemistry Volume: 26 Issue: 2 Pages: 463-469
  • DOI: 10.1016/j.bmc.2017.12.007
  • Peer Reviewed
• [Journal Article] 123I-Labeled oxLDL Is Widely Distributed Throughout the Whole Body in Mice (2017)
  • Author(s): Nakano Atushi、Kawashima Hidekazu、Miyake Yoshinori、Zeniya Tsutomu、Yamamoto Akihide、Koshino Kazuhiro、Temma Takashi、Fukuda Tetsuya、Fujita Yoshiko、Kakino Akemi、Kanaya Shigehiko、Sawamura Tatsuya、Iida Hidehiro
  • Journal Title: Nuclear Medicine and Molecular Imaging Volume: 52 Issue: 2 Pages: 144-153
  • DOI: 10.1007/s13139-017-0497-2
  • Peer Reviewed / Open Access
• [Journal Article] Efficacy of Combination Therapy with MET and VEGF Inhibitors for MET-overexpressing Glioblastoma. (2017)
  • Author(s): Takeshi Okuda, Takayuki Tasaki, Susumu Nakata, Kimihiro Yamashita, Hiromasa Yoshioka, Shuichi Izumoto, Amami Kato, Mitsugu Fujita.
  • Journal Title: Anticancer Research Volume: 37 Issue: 7 Pages: 3871-3876
  • DOI: 10.21873/anticanres.11767
  • Peer Reviewed / Open Access
• [Journal Article] Development of 111In-labeled exendin(9-39) derivatives for single-photon emission computed tomography imaging of insulinoma. (2017)
  • Author(s): Hiroyuki Kimura, Hirokazu Matsuda, Yu Ogawa, Hiroyuki Fujimoto, Kentaro Toyoda, Naotaka Fujita, Kenji Arimitsu, Keita Hamamatsu, Yusuke Yagi, Masahiro Ono, Nobuya Inagaki, Hideo Saji.
  • Journal Title: Bioorganic and Medicinal Chemistry Volume: 25 Issue: 4 Pages: 1406-1412
  • DOI: 10.1016/j.bmc.2016.12.051
  • Peer Reviewed
• [Presentation] F-18標識ボロン酸誘導体による鈴木カップリング反応を用いた新規F-18標識法の開発 (2018)
  • Author(s): 屋木祐亮、有光健治、平野圭市、安井裕之、木村寛之
  • Organizer: 第58回日本核医学会学術総会
• [Presentation] F-18 標識ボロン酸誘導体を用いた新規F-18 標識法の開発 (2018)
  • Author(s): 屋木祐亮、有光健治、平野圭市、安井裕之、木村寛之
  • Organizer: 第41回フッ素化学討論会
• [Presentation] 18F標識STZ誘導体の体内分布に関する基礎的評価 (2018)
  • Author(s): 有光健治、木村寛之、屋木祐亮、佐治英郎、安井裕之
  • Organizer: 日本薬学会第138年会
• [Presentation] 脳腫瘍幹細胞マウスモデルを用いたアセトゲニン誘導体新規がん治療薬開発. (2018)
  • Author(s): 東馬智未, 茂山千愛美, 小島直人, 岩崎仁志, 安藤翔太, 藤田貢, 谷口恵香, 飯居宏美, 吉貴達寛, 中田晋
  • Organizer: 日本薬学会第138年会（金沢）
• [Presentation] Stat5b は発がんマウスモデル由来膠芽腫幹様細胞の増殖促進に寄与している. (2017)
  • Author(s): 茂山千愛美, 藤田貢, 飯居宏美, 谷口恵香, 吉貴達寛, 中田晋
  • Organizer: 第76回 日本癌学会学術総会(横浜)
• [Presentation] 銅および亜鉛を含有する多核金属錯体のB16/BL6細胞への殺細胞活性および抗腫瘍効果. (2017)
  • Author(s): 二木珠希、平内孝典、中川結稀、内藤行喜、安井裕之
  • Organizer: 日本薬学会第137年会 (宮城)
• [Presentation] コラーゲン様3重らせんペプチド結合型白金錯体の体内動態解析と腹膜播種担がんマウスにおける抗腫瘍効果. (2017)
  • Author(s): 林 梨沙、増田 亮、能勢 博、田口晃弘、林 良雄、小出隆規、安井裕之
  • Organizer: 第67回日本薬学会近畿支部総会・大会 (兵庫)