Protein complex analysis of transcriptional factor KLF, and development of a low molecular weight compound that inhibits KLF5 transcriptional activity.

• Project/Area Number: 15H04824
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: Jichi Medical University
• Principal Investigator: Nagai Ryozo 自治医科大学, 医学部, 学長 (60207975)
• Co-Investigator(Kenkyū-buntansha): 相澤 健一 自治医科大学, 医学部, 准教授 (70436484) ; 仲矢 丈雄 自治医科大学, 医学部, 講師 (80512277)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000); Fiscal Year 2017: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000); Fiscal Year 2016: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000); Fiscal Year 2015: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
• Keywords: KLF5 / 蛋白間相互作用阻害薬 / 分子創薬 / 心不全 / 癌 / 心血管リモデリング / KLF / In vivo蛋白複合体解析 / 心臓リモデリング / 大腸癌 / KLF5阻害薬 / 心‐脳‐腎臓器連関 / 蛋白複合体

Outline of Final Research Achievements

From our previous studies, KLF5 is a potential therapeutic target for cardiovascular disease and cancer. However, structure-based drug design of KLF5 inhibitors has not been successful because KLF5 is an intrinsically disordered protein. Therefore, we have analyzed the structure of KLF5 in silico and synthesized several low molecular weight compounds which mimic the a-helical region of KLF5 which is suggested to be involved in protein-protein interactions. We have found several compounds to inhibit KLF5 function as shown by inhibition of cell growth of smooth muscle cells and colorectal cancer cells. The compounds were found to reduce protein levels of KLF5 without altering KLF5 mRNA levels, suggesting degradation of KLF5 was accelerated in the presence of the compounds. We further found that the compounds can improve heart failure caused by aortic constriction. We conclude these compounds to be promising new therapeutic drugs for cardiovascular diseases as well as cancers.

Research Products

• [Journal Article] High-Dose Versus Low-Dose Pitavastatin in Japanese Patients With Stable Coronary Artery Disease (REAL-CAD) (2018)
  • Author(s): Taguchi Isao、Iimuro Satoshi、Iwata Hiroshi、et.al 、Nagai Ryozo
  • Journal Title: Circulation Volume: 137 Issue: 19 Pages: 1997-2009
  • DOI: 10.1161/circulationaha.117.032615
  • Peer Reviewed / Open Access
• [Journal Article] A heart-brain-kidney network controls adaptation to cardiac stress through tissue macrophage activation and cellular communication (2017)
  • Author(s): Fujiu K, Shibata M, Nakayama Y, Ogata F, Matsumoto S, Noshita K, Iwami S, Nakae S, Komuro I, Nagai R, Manabe I
  • Journal Title: Nature Medicine Volume: 印刷中 Issue: 5 Pages: 611-622
  • DOI: 10.1038/nm.4326
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Klf5 maintains the balance of primitive endoderm versus epiblast specification during mouse embryonic development by suppression of Fgf4 (2017)
  • Author(s): Azami Takuya、Waku Tsuyoshi、Matsumoto Ken、Jeon Hyojung、Muratani Masafumi、Kawashima Akihiro、Yanagisawa Jun、Manabe Ichiro、Nagai Ryozo、Kunath Tilo、Nakamura Tomonori、Kurimoto Kazuki、Saitou Mitinori、Takahashi Satoru、Ema Masatsugu
  • Journal Title: Development Volume: 144 Issue: 20 Pages: 3706-3718
  • DOI: 10.1242/dev.150755
  • NAID: 120007134671
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Multi-scale, tailor-made heart simulation can predict the effect of cardiac resynchronization therapy (2017)
  • Author(s): Okada Jun-ichi、Washio Takumi、Nakagawa Machiko、Watanabe Masahiro、Kadooka Yoshimasa、Kariya Taro、Yamashita Hiroshi、Yamada Yoko、Momomura Shin-ichi、Nagai Ryozo、Hisada Toshiaki、Sugiura Seiryo
  • Journal Title: Journal of Molecular and Cellular Cardiology Volume: 108 Pages: 17-23
  • DOI: 10.1016/j.yjmcc.2017.05.006
  • Peer Reviewed
• [Journal Article] Identification of M2 macrophages in anterior pituitary glands of normal rats and rats with estrogen-induced prolactinoma. (2017)
  • Author(s): Fujiwara K, Yatabe M, Tofrizal A, Jindatip D, Yashiro T, Nagai R.
  • Journal Title: Cell and Tissue Research Volume: 368 Issue: 2 Pages: 371-378
  • DOI: 10.1007/s00441-016-2564-x
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Islet inflammation in type 2 diabetes and physiology. (2017)
  • Author(s): Eguchi K, Nagai R.
  • Journal Title: Journal of Clinical Investigation Volume: 127 Issue: 1 Pages: 14-23
  • DOI: 10.1172/jci88877
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] KLF15 Enables Rapid Switching between Lipogenesis and Gluconeogenesis during Fasting. (2016)
  • Author(s): Takeuchi Y, Yahagi N, Aita Y, Murayama Y, Sawada Y, Piao X, Toya N, Oya Y, Shikama A, Takarada A, Masuda Y, Nishi M, Kubota M, Izumida Y, Yamamoto T, Sekiya M, Matsuzaka T, Nakagawa Y, Urayama O, Kawakami Y, Iizuka Y, Gotoda T, Itaka K, Kataoka K, Nagai R, Kadowaki T, Yamada N, Lu Y, Jain MK, and Shimano H
  • Journal Title: Cell Rep. Volume: 16 Issue: 9 Pages: 2373-2386
  • DOI: 10.1016/j.celrep.2016.07.069
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Choroidal Neovascularization Is Inhibited in Splenic-Denervated or Splenectomized Mice with a Concomitant Decrease in Intraocular Macrophage. (2016)
  • Author(s): Tan X, Fujiu K, Manabe I, Nishida J, Yamagishi R, Terashima Y, Matsushima K, Kaburaki T, Nagai R, Yanagi Y.
  • Journal Title: PLoS One Volume: 11 Issue: 8 Pages: e0160985-e0160985
  • DOI: 10.1371/journal.pone.0160985
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Association between the docosahexaenoic acid to arachidonic acid ratio and acute coronary syndrome: a multicenter observational study. (2016)
  • Author(s): Nishizaki Y, Shimada K, Tani S, Ogawa T, Ando J, Takahashi M, Yamamoto M, Shinozaki T, Miyazaki T, Miyauchi K, Nagao K, Hirayama A, Yoshimura M, Komuro I, Nagai R, Daida H.
  • Journal Title: BMC Cardiovascular Disorders Volume: 16 Issue: 1 Pages: 143-143
  • DOI: 10.1186/s12872-016-0299-y
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Influence of periostin-positive cell-specific Klf5 deletion on aortic thickening in DOCA-salt hypertensive mice. (2016)
  • Author(s): Zempo H, Suzuki JI, Ogawa M, Watanabe R, Fujiu K, Manabe I, Conway SJ, Taniyama Y, Morishita R, Hirata Y, Isobe M, Nagai R.
  • Journal Title: Hypertens Res Volume: 39 Issue: 11 Pages: 764-768
  • DOI: 10.1038/hr.2016.65
  • Peer Reviewed / Open Access
• [Journal Article] HIF-1alpha-PDK1 axis-induced active glycolysis plays an essential role in macrophage migratory capacity (2016)
  • Author(s): Semba, H., Takeda, N., Isagawa, T., Sugiura, Y., Honda, K., Wake, M., Miyazawa, H., Yamaguchi, Y., Miura, M., Jenkins, DM., Choi, H., Kim, JW., Asagiri, M., Cowburn, AS., Abe, H., Soma, K., Koyama, K., Katoh, M., Sayama, K., Goda, N., Johnson, RS., Manabe, I., Nagai, R., Komuro, I.
  • Journal Title: Nature Communications Volume: 7 Issue: 1 Pages: 11635-11635
  • DOI: 10.1038/ncomms11635
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Excess Lymphangiogenesis Cooperatively Induced by Macrophages and CD4D T Cells Drives the Pathogenesis of Lymphedema (2016)
  • Author(s): Ogata F
  • Journal Title: Journal of Investigative Dermatology Volume: 136 Issue: 3 Pages: 706-714
  • DOI: 10.1016/j.jid.2015.12.001
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Ataxia telangiectasia mutated in cardiac fibroblasts regulates doxorubicin-induced cardiotoxicity (2016)
  • Author(s): Zhan H, Aizawa K, Sun JQ, Tomida S, Otsu K, Conway S, McKinnon P, Manabe I, Komuro I, Miyagawa K, Nagai R, Suzuki T
  • Journal Title: Cardiovasc. Res. Volume: 110 Issue: 1 Pages: 85-95
  • DOI: 10.1093/cvr/cvw032
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [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: 日本癌学会
  • Place of Presentation: パシフィコ横浜 (横浜、神奈川)
  • Year and Date: 2016-10-06
• [Presentation] Future Directions for KLF Research (2016)
  • Author(s): 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 Village, CO, USA)
  • Year and Date: 2016-08-07
  • Int'l Joint Research / Invited
• [Presentation] The protein interaction inhibitors of KLF5 suppress Wnt signalactivation selectively in colorectal cancer cells (2016)
  • Author(s): Takeo Nakaya, Hirofumi Nakano, Masaji Kasai, Atsushi Yoshimori, Akira Tanaka, Hiroyuki Kouji, 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 Village, CO, USA)
  • Year and Date: 2016-08-07
  • Int'l Joint Research