Novel therapy for neurological disorders by protein-protein interaction inhibitor

• Project/Area Number: 16K15317
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Applied pharmacology
• Research Institution: Osaka University
• Principal Investigator: SASAKI Tsutomu 大阪大学, 医学系研究科, 講師 (20534879)
• Co-Investigator(Kenkyū-buntansha): 平田 佳之 大阪薬科大学, 薬学部, 助教 (00745854) ; 長岡 康夫 関西大学, 化学生命工学部, 教授 (90243039)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: PPI阻害剤 / p53 / MDM2 / MDMX / 神経細胞 / 血管内皮 / 血管内皮細胞 / 血液脳関門 / 蛋白相互作用阻害剤 / 神経保護剤 / 低分子化合物 / 脳虚血 / パーキンソン病 / 脳神経疾患 / 蛋白質 / 蛋白蛋白相互作用 / 創薬化学 / トランスレーショナルリサーチ

Outline of Final Research Achievements

Protein-protein interactions (PPI) are fundamental to cell biological processes and are often dysregulated in various neurological disorders. PPI hence represent a huge class of therapeutic targets and modulation of PPI with small molecules has becoming increasingly important in drug discovery. To screen for novel neuroprotective small-molecule PPI inhibitors in in vitro and in vivo Parkinson’s disease (PD) and stroke. PPI inhibitors, with protective effects against MPP+-induced neuronal death in in vitro model were identified. Furthermore, oral administration of PPI inhibitors before MPTP mitigated MPTP-induced loss of dopaminergic neurons in substantia nigra, compared with saline-treated control mice. Also, PPI inhibitors mitigated ischemic stroke, resulting in enhanced functional outcome. The discovery of these small-molecule p53/negative regulator-interaction inhibitors with neuroprotective properties may pave the way to new therapeutic strategies for PD or stroke treatment.

Research Products

• [Journal Article] New 5-Aryl-Substituted 2-Aminobenzamide-Type HDAC Inhibitors with a Diketopiperazine Group and Their Ameliorating Effects on Ischemia-Induced Neuronal Cell Death. (2018)
  • Author(s): Hirata Y, Sasaki T, Kanki H, Choong CJ, Nishiyama K, Kubo G, Hotei A, Taniguchi M, Mochizuki H, Uesato S.
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 1400-1400
  • DOI: 10.1038/s41598-018-19664-9
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Febuxostat ameliorates secondary progressive experimental autoimmune encephalomyelitis by restoring mitochondrial energy production in a GOT2-dependent manner (2017)
  • Author(s): Honorat Josephe A.、Nakatsuji Yuji、Shimizu Mikito、Kinoshita Makoto、Sumi-Akamaru Hisae、Sasaki Tsutomu、Takata Kazushiro、Koda Toru、Namba Akiko、Yamashita Kazuya、Sanda Eri、Sakaguchi Manabu、Kumanogoh Atsushi、Shirakura Takashi、Tamura Mizuho、Sakoda Saburo、Mochizuki Hideki、Okuno Tatsusada
  • Journal Title: PLoS One Volume: 12 Issue: 11 Pages: e0187215-e0187215
  • DOI: 10.1371/journal.pone.0187215
  • Peer Reviewed / Open Access
• [Journal Article] Plasma D-dimer levels and ischaemic lesions in multiple vascular regions can predict occult cancer in patients with cryptogenic stroke. (2017)
  • Author(s): Gon Y, Sakaguchi M, Takasugi J, Kawano T, Kanki H, Watanabe A, Oyama N, Terasaki Y, Sasaki T, Mochizuki H.
  • Journal Title: Eur J Neurol. Volume: Mar;24(3) Issue: 3 Pages: 503-508
  • DOI: 10.1111/ene.13234
  • Peer Reviewed
• [Journal Article] Potential Application of 5-Aryl-Substituted 2-Amino- benzamide Type of HDAC1/2-Selective Inhibitors to Pharmaceuticals. (2016)
  • Author(s): Uesato S, Hirata Y, Sasaki T.
  • Journal Title: Current Pharmaceutical Design Volume: 22, Dec Issue: 40 Pages: 6149-6159
  • DOI: 10.2174/1381612822666161208143417
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Discovery of new low-molecular-weight p53-Mdmx disruptors and their anti-cancer activities (2016)
  • Author(s): Uesato, S.; Matsuura, Y.; Matsue, S.; Sumiyoshi, T.; Hirata, Y.; Takemoto, S.; Kawaratani, Y.; Yamai, Y.; Ishida, K.; Sasaki, T.; Enari, M.
  • Journal Title: Bioorganic & Medicinal Chemistry Volume: 24 Issue: 8 Pages: 1919-1926
  • DOI: 10.1016/j.bmc.2016.03.021
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] 脳虚血時における分泌型Lynx1の動態の検討 (2018)
  • Author(s): 佐々木勉、神吉 秀明、松村 成暢、河野 友裕、上里 新一、坂口 学、望月秀樹
  • Organizer: 第43回日本脳卒中学会学術集会（STROKE 2018）
• [Presentation] CRTC2 played important role for ischemic stroke (2018)
  • Author(s): Hideaki Kanki, Tsutomu Sasaki, Manabu Sakaguchi, Hideki Mochizuki
  • Organizer: 第59回日本神経学会学術大会
• [Presentation] Sasaki T, Kanki H, Hirata Y, Yen H, Kawano T1, Sakaguchi M, Uesato S and Mochizuki H (2018)
  • Author(s): New Type HDAC Inhibitors with a Diketopiperazine Group and Ameliorating Effects on Ischemic Injury
  • Organizer: 第59回日本神経学会学術大会
• [Presentation] The mechanisms of neuroprotective effects of isoform selective HDAC inhibitors for brain ischemia. (2017)
  • Author(s): Sasaki T, Kanki H, Choong CJ, Baba K, Hirata Y, Sakaguchi M, Uesato S and Mochizuki H
  • Organizer: The XXIII World Congress of Neurology (WCN 2017)
  • Int'l Joint Research
• [Presentation] Screening for small-molecule inhibitors of protein-protein interaction (PPI) with neuroprotective effect in experimental PD (2017)
  • Author(s): Choong CJ, Sasaki T, Baba K, Hirata Y, Uesato S and Mochizuki H
  • Organizer: The XXIII World Congress of Neurology (WCN 2017)
  • Int'l Joint Research
• [Presentation] Small-molecule p53/negative regulator-interaction inhibitors confer neuroprotection against MPP+/MPTP-induced neurotoxicity in experimental PD (2017)
  • Author(s): Chi-Jing Choong, Tsutomu Sasaki, Hideki Hayakawa, Kousuke Baba, Yoshiyuki Hirata, Shinichi Uesato, and Hideki Mochizuki
  • Organizer: Suzhou Basic Scientists Summer School 2017
  • Int'l Joint Research
• [Presentation] CRTC2 enhanced angiogenesis and endothelial function (2017)
  • Author(s): Hideaki Kanki, Tsutomu Sasaki, Manabu Sakaguchi, Hideki Mochizuki
  • Organizer: The XXIII World Congress of Neurology (WCN 2017)
  • Int'l Joint Research