Screening of phosphorylation dependent 14-3-3 binding inhibitors

• Project/Area Number: 24510320
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Chemical biology
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: WATANABE Nobumoto 国立研究開発法人理化学研究所, 環境資源科学研究センター, ユニットリーダー (90221689)
• Project Period (FY): 2012-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2012: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: タンパク質間相互作用 / 小分子化合物 / １４－３－３タンパク質 / タンパク質リン酸化 / 14-3-3タンパク質 / 細胞周期 / 14-3-3

Outline of Final Research Achievements

A high-throughput screening (HTS) system was developed and employed to the chemical libraries of the RIKEN NPDepo to identify small molecule compounds with 14-3-3 protein-protein interaction inhibitory activity. We identified small molecule inhibitors of 14-3-3 dependent interaction. While most of these hit compounds inhibited some isoforms of 14-3-3 interaction but not those of other isoforms, one compound was found to inhibit all the 14-3-3 isoform dependent binding. This compound had modest growth inhibitory activity of human cancer cells. To our knowledge, small molecule inhibitor for all the 14-3-3 isoform interaction is not reported yet. Our study demonstrates a potential strategy of inhibiting 14-3-3 interaction in human cancers to induce their growth inhibition using small molecule inhibitors.

Research Products

• [Journal Article] Creation of chimeric human/rabbit APOBEC1 with HIV-1 restriction and DNA mutation activities (2016)
  • Author(s): Ikeda T, Ong EBB, Watanabe N, Sakaguchi N, Maeda K, and Koito A.
  • Journal Title: Sci. Reports Volume: 6 Issue: 1 Pages: 19035-19035
  • DOI: 10.1038/srep19035
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Small molecules that target phosphorylation dependent protein-protein interaction (2016)
  • Author(s): Watanabe N, Osada H
  • Journal Title: Bioorg Med Chem Volume: 印刷中 Issue: 15 Pages: 30171-30177
  • DOI: 10.1016/j.bmc.2016.03.023
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Inhibition of malaria parasite growth by quinomycin A and its derivatives through DNA-intercalating activity. (2015)
  • Author(s): Hayase H, Watanabe N, Lim CL, Nogawa T, Komatsuya K, Kita K, Osada H.
  • Journal Title: Biosci Biotechnol Biochem Volume: 79 Issue: 4 Pages: 633-635
  • DOI: 10.1080/09168451.2014.987205
  • Peer Reviewed / Open Access
• [Journal Article] In silico investigation of a HIV-1 Vpr inhibitor binding site: Potential for virtual screening and anti-HIV drug design. (2014)
  • Author(s): 38.Choi, SB.; Choong, YS., Saito, A., Wahab, H., Najimudin, N., Watanabe, N., Osada, H., and Ong, E.
  • Journal Title: Mol. Infomatics Volume: 33 Issue: 11-12 Pages: 742-748
  • DOI: 10.1002/minf.201400080
  • Peer Reviewed
• [Journal Article] PI 3-kinase-dependent phosphorylation of Plk1-Ser99 promotes its association with 14-3-3γ and is required for metaphase-anaphase transition. (2013)
  • Author(s): Kasahara, K., Goto, H., Izawa, I., Kiyono, T., Watanabe, N., Elowe, S., Nigg, EA., and Inagaki, M.
  • Journal Title: Nat. Commun. Volume: 4 Issue: 11 Pages: 1882-1882
  • DOI: 10.1111/cas.12246
  • Peer Reviewed
• [Journal Article] 細胞周期を制御するリン酸化依存タンパク質間相互作用阻害剤の開発 (2013)
  • Author(s): 渡辺信元
  • Journal Title: 実験医学 Volume: 31 Pages: 297-302
• [Journal Article] 新たな抗がん剤探索を加速する新スクリーニング技術 (2013)
  • Author(s): 長田裕之, 二村友史, 渡辺信元, 近藤恭光
  • Journal Title: 細胞工学 Volume: 32 Pages: 655-659
• [Journal Article] リン酸化依存性タンパク質間相互作用阻害物質の探索と抗がん剤への展開 (2013)
  • Author(s): 渡辺信元，長田裕之
  • Journal Title: がん基盤生物学-革新的シーズ育成に向けて- Volume: 1 Pages: 305-310
• [Journal Article] Boronic acid inhibitors of acyl protein thioesterase 1 and 2 (2013)
  • Author(s): Zimmermann, T.J., Burger, M., Tashiro, E., Kondoh, Y., Martinez, N.E., Gormer, K., Rosin-steiner, S., Shimizu, T. Ozaki, S., Mikoshiba, K., Watanabe, N., Hall, D., Vetter, I.R., Osada, H., Hedberg, C., & Waldmann, H
  • Journal Title: ChemBioChem Volume: 14 Issue: 1 Pages: 115-122
  • DOI: 10.1002/cbic.201200571
  • Peer Reviewed
• [Journal Article] PI 3-kinase-dependent phosphorylation of Plk1-Ser99 promotes association with 14-3-3γ and is required for metaphase-anaphase transition (2013)
  • Author(s): Kasahara, K., Goto, H., Izawa, I., Kiyono, T., Watanabe, N., Elowe, S., Nigg, E.A. and Inagaki, M.
  • Journal Title: Nat. Commun. Volume: 4 Issue: 1 Pages: 1882-1882
  • DOI: 10.1038/ncomms2879
  • Peer Reviewed / Open Access
• [Journal Article] Crystal structure of the predicted phospholipase LYPLAL1 reveals unexpected functional plasticity despite close relationship to acyl protein thioesterases (2012)
  • Author(s): Burger, M., Zimmermann, T. J., Kondoh, Y., Stege, P., Watanabe, N., Osada, H., Waldmann, H. & Vetter, I. R
  • Journal Title: Journal of Lipid Research Volume: 53 Issue: 1 Pages: 43-50
  • DOI: 10.1194/jlr.m019851
  • Peer Reviewed
• [Journal Article] Phosphorylation-dependent protein-protein interaction modules as potential molecular targets for cancer therapy (2012)
  • Author(s): Watanabe, N., Osada H
  • Journal Title: Curr. Drug Targets Volume: 13 Issue: 13 Pages: 1654-1658
  • DOI: 10.2174/138945012803530035
  • Peer Reviewed
• [Journal Article] Morphobase, an encyclopedic cell morphology database, and its use for drug target identification. (2011)
  • Author(s): Futamura, Y., et al.
  • Journal Title: Chem Biol. Volume: 19 Issue: 12 Pages: 1620-1630
  • DOI: 10.1016/j.chembiol.2012.10.014
  • Peer Reviewed
• [Presentation] Discovery and analyses of 14-3-3 protein-protein interaction inhibitors identified by high throughput screening (2016)
  • Author(s): Nobumoto Watanabe, Hiroyuki Osada
  • Organizer: Tenth AACR-JCA Joint Conference on Breakthroughs in Cancer Research: From Biology to Therapeutics
  • Place of Presentation: Maui, USA
  • Year and Date: 2016-02-16
  • Int'l Joint Research
• [Presentation] Small Molecule Inhibitors of ubiquitin-proteasome dependent degradation of p27Kip1 identified by high throughput screening (2013)
  • Author(s): N. Watanabe, LC Ooi, and H. Osada
  • Organizer: Ninth AACR-Japanese Cancer Association Joint Conference: Breakthroughs in Basic and Translational Cancer Research
  • Place of Presentation: Maui, HI, USA
• [Presentation] High-Throughput Screening to Identify Small Molecule Inhibitors of p27Kip1 Ubiquitination (2012)
  • Author(s): N. Watanabe, LC Ooi, and H. Osada
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: マリンメッセ福岡、福岡
• [Presentation] Screening of inhibitors of p27Kip1 ubiquitination by SCFSkp2 (SCFSkp2による p27Kip1のユビキチン化阻害物質の探索)
  • Author(s): 渡辺 信元, 新家 一男, 長田 裕之
  • Organizer: 第72回 日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
• [Presentation] 細胞周期阻害物質のハイスループット探索と創薬への応用
  • Author(s): 渡辺信元
  • Organizer: 第17回日本がん分子標的治療学会学術集会シンポジウム
  • Place of Presentation: 国立京都国際会館
  • Invited
• [Presentation] 生物機能解析のためのケミカルバイオロジー基盤技術
  • Author(s): 渡邉信元
  • Organizer: 第3回CSJ化学フェスタ
  • Place of Presentation: タワーホール船堀
  • Invited