Elucidation of the KLF protein complex in intestinal tissues and development of new drugs to suppress protein-protein interactions for the treatment of colorectal cancer

• Project/Area Number: 16K08718
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Jichi Medical University
• Principal Investigator: Nakaya Takeo 自治医科大学, 医学部, 講師 (80512277)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: KLF5 / 蛋白間相互作用 / 大腸癌 / 癌分子創薬 / 天然変性蛋白 / 転写因子 / 心不全 / ミトコンドリア / 蛋白間相互作用阻害 / 蛋白間相互作用阻害薬 / 癌選択的抑制 / KLF5阻害薬 / 新規抗癌薬 / 腫瘍 / 新規癌治療開発

Outline of Final Research Achievements

We found that KLF5 is essential for tumorigenesis from intestinal epithelial stem cells, and is a promising molecular target for cancer treatment. However, it has been difficult to develop inhibitors of KLF due to the lack of clarification of their 3D structure. We have developed new anticancer drugs, small molecule compounds that are expected to inhibit the protein-protein interactions of KLF5. The results showed that the compounds selectively suppressed human colon cancer cells without damaging normal human cell, and suppressed transplanted human colorectal cancer cell tumors in mice. The compounds suppressed the quantities of KLF5 and other proteins in cancer cells, but not in normal cells. We have discovered a structure-activity relationship between chemical structure and tumor cell suppression, and have created compounds with high tumor suppression potential. We identified the binding proteins of the compounds and elucidated the molecular mechanism of action.

Academic Significance and Societal Importance of the Research Achievements

がんゲノム解析に基づきゲノム異常に応じた分子標的薬を用いるがんprecision medicineが求められている。しかし、がん原因因子の多くは、立体構造を解明できない天然変性蛋白であり、立体構造に基づく分子標的薬の開発が難しい。また、がん原因因子の多くは、低分子化合物でないと到達し作用できない核内因子である。このため、がん原因因子の多くに対し分子標的薬が開発されておらず、がんゲノム解析を行っても新たに有効な治療薬が見出される率は低いままである。本研究は、よい分子標的薬のなかった天然変性蛋白、核内因子に対しがん分子創薬を可能にし、進行がん患者の予後改善に貢献すると期待される。

Research Products

• [Journal Article] Cardiac myofibroblast engulfment of dead cells facilitates recovery after myocardial infarction. (2017)
  • Author(s): Michio Nakaya,Kenji Watari,Mitsuru Tajima,Takeo Nakaya,Shoichi Matsuda,Hiroki Ohara,Hiroaki Nishihara,Hiroshi Yamaguchi,Akiko Hashimoto,Mitsuho Nishida,Akiomi Nagasaka,Yuma Horii,Hiroki Ono,Gentaro Iribe,Ryuji Inoue,Makoto Tsuda,Kazuhide Inoue,Akira Tanaka,Masahiko Kuroda,Shigekazu Nagata,Hitoshi Kurose
  • Journal Title: Journal of Clinical Investigation Volume: 127 Issue: 1 Pages: 383-401
  • DOI: 10.1172/jci83822
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Stimulation of cellular senescent processes, including secretory phenotypes and anti-oxidant responses, after androgen deprivation therapy in human prostate cancer (2017)
  • Author(s): Kawata H, Kamiakito T, Nakaya T, Komatsubara M, Komatsu K, Morita T, Nagao Y, Tanaka A
  • Journal Title: Journal of Steroid Biochemistry & Molecular Biology Volume: 165 Pages: 219-227
  • DOI: 10.1016/j.jsbmb.2016.06.007
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Giant solitary fibrous tumor of the pleura with high-grade sarcomatous overgrowth accompanied by lipid-rich, rhabdomyosarcomatous, and pleomorphic components (2017)
  • Author(s): Nakaya Takeo、Oshiro Hisashi、Takigami Ayako、Kanai Yoshihiko、Tetsuka Kenji、Hagiwara Koichi、Fujii Hirofumi、Endo Shunsuke、Tanaka Akira
  • Journal Title: Medicine Volume: 96 Issue: 50 Pages: e8926-e8926
  • DOI: 10.1097/md.0000000000008926
  • Peer Reviewed / Open Access
• [Journal Article] Renal dysplasia characterized by prominent cartilaginous metaplasia lesions in VACTERL association (2017)
  • Author(s): Nakaya Takeo、Hyuga Taiju、Tanaka Yukichi、Kawai Shina、Nakai Hideo、Niki Toshiro、Tanaka Akira
  • Journal Title: Medicine Volume: 96 Issue: 15 Pages: e6499-e6499
  • DOI: 10.1097/md.0000000000006499
  • Peer Reviewed / Open Access
• [Journal Article] Ectopic respiratory mucosa in the skin which showed the repetitive distribution of ciliated bronchogenic epithelia and squamous metaplasia (2017)
  • Author(s): Nakano Naomi、Nakaya Takeo、Kamiya Koji、Komine Mayumi、Murata Satoru、Kawata Hirotoshi、Yokoyama Shigeo、Tanaka Akira、Ohtsuki Mamitaro
  • Journal Title: The Journal of Dermatology Volume: 44 Issue: 11 Pages: 1327-1328
  • DOI: 10.1111/1346-8138.13697
  • Peer Reviewed
• [Presentation] Small molecules mimicking KLF5 structure suppresses cancer cells in both in vivo and vitro without damaging normal cells. (2018)
  • Author(s): Nakaya T, Tsuji K, Tanaka A, Nagai R.
  • Organizer: 6th International Conference on Biology and Pathobiology of KLF/Sp Transcription Factors
  • Int'l Joint Research / Invited
• [Presentation] Small molecular mimicries of KLF5 selectively suppress the survival and Wnt-KLF5 signaling of colorectal cancer cells. (2016)
  • Author(s): 仲矢丈雄、中野洋文、河西政次、吉森篤史、田中亨、小路弘行、永井良三
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜 (横浜、神奈川)
  • Year and Date: 2016-10-06
• [Presentation] The protein interaction inhibitors of KLF5 suppress Wnt signal activation selectively in colorectal cancer cells (2016)
  • Author(s): Takeo Nakaya, Hirofumi Nakano, Masaji Kasai, Atsushi Yoshimori, Akira Tanaka, Ryozo Nagai
  • Organizer: FASEB Science Research Conference ”KLF and Sp Transcription Factors in Disease and Regenerative Medicine"
  • Place of Presentation: Snowmass Base Village Conference Center (Snowmass, CO, USA)
  • Year and Date: 2016-08-07
  • Int'l Joint Research