Molecular basis for the development of novel STAT3 inhibitors

• Project/Area Number: 26430166
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor therapeutics
• Research Institution: University of Shizuoka
• Principal Investigator: Asai Akira 静岡県立大学, 薬学研究院, 教授 (60381737)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: STAT3 / SH2 / シグナル伝達 / 免疫チェックポイント / IDO1 / PD-L1 / 抗がん / 転写制御因子 / キナーゼ / 抗がん物質 / 併用効果 / 抗がん剤

Outline of Final Research Achievements

We previously discovered a novel STAT3 inhibitor, STX-COMP, which is expected to be a new anticancer drug candidate. The investigation on the mode of action of STX-COMP and identification of its susceptibility factors are important issues for the purpose of clinical use of this unique compound in future. In this study, we demonstrated STX-COMP inhibits STAT3 dimerization and thereby suppress the transcriptional activity in cancer cells. The profile of this compound in the various bioassays was proved to be quite different from other known STAT3 inhibitors. Furthermore, we revealed that STX-COMP not only inhibited the growth of cancer cells but also suppressed the expression of immune checkpoint factors such as PD-L1 and IDO1 in cancer cells. To identify the biomarker for STX-COMP, we refined the susceptibility factor candidates to the STAT3 inhibition by using the siRNA library. The kinase inhibitors that might be useful for the combination therapies with STX-COMP were also discovered.

Research Products

• [Int'l Joint Research] ラドバウト大学(オランダ)
• [Int'l Joint Research] ミラノ大学(イタリア)
• [Journal Article] Direct inhibition of STAT signaling by platinum drugs contributes to their anti-cancer activity (2017)
  • Author(s): Hato SV, Figdor CG, Takahashi S, Pen AE, Halilovic A, Bol KF, Vasaturo A, Inoue Y, de Haas N, Verweij D, Van Herpen CML, Kaanders JH, van Krieken JHJM, Van Laarhoven HWM, Hooijer GKJ, Punt CJA, Asai A, de Vries IJM, Lesterhuis WJ.
  • Journal Title: Oncotarget Volume: in press
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Inhibition of STAT3 by Anticancer Drug Bendamustine (2017)
  • Author(s): Iwamoto K, Uehara Y, Inoue Y, Taguchi K, Muraoka D, Ogo N, Matsuno K, Asai A.
  • Journal Title: PLoS One Volume: １２ Issue: 1 Pages: e0170709-e0170709
  • DOI: 10.1371/journal.pone.0170709
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] An in vivo active 1,2,5-oxadiazole Pt(II) complex: a promising anticancer agent endowed with STAT3 inhibitory properties (2017)
  • Author(s): Porta F, Facchetti G, Ferri N, Gelain A, Meneghetti F, Villa S, Barlocco D, Masciocchi D, Asai A, Miyoshi N, Marchianò S, Kwon BM, Gandin V, Marzano C, Rimoldi I.
  • Journal Title: Eur J Med Chem Volume: １３１ Pages: 196-206
  • DOI: 10.1016/j.ejmech.2017.03.017
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Methanethiosulfonate derivatives as ligands of the STAT3-SH2 domain (2017)
  • Author(s): Gabriele E, Ricci C, Ferri N, Asai A, Sparatorea A
  • Journal Title: J Enzyme Inhib Med Chem Volume: ３２ Issue: 1 Pages: 337-344
  • DOI: 10.1080/14756366.2016.1252757
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Combination of a STAT3 Inhibitor and an mTOR Inhibitor Against a Temozolomide-resistant Glioblastoma Cell Line (2017)
  • Author(s): Miyata H, Ashizawa T, Iizuka A, Kondou R, Nonomura C, Sugino T, Urakami K, Asai A, Hayashi N, Mitsuya K, Nakasu Y, Yamaguchi K, Akiyama Y.
  • Journal Title: Cancer Genomics Proteomics Volume: １４ Issue: 1 Pages: 83-91
  • DOI: 10.21873/cgp.20021
  • Peer Reviewed / Open Access
• [Journal Article] 新薬のためのコンセプトデザイン (2017)
  • Author(s): 浅井章良
  • Journal Title: Biophilia Volume: 66 Pages: 22-28
• [Journal Article] Identification of a new STAT3 dimerization inhibitor through a pharmacophore-based virtual screening approach (2015)
  • Author(s): Poli G, Gelain A, Porta F, Asai A, Martinelli A, Tuccinardi T
  • Journal Title: J Enzyme Inhib Med Chem Volume: Aug26 Issue: 6 Pages: 1-7
  • DOI: 10.3109/14756366.2015.1079184
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Ureido-pyridazinone derivatives: Insights into the structural and conformational properties for STAT3 inhibition (2015)
  • Author(s): Meneghetti F, Villa S, Masciocchi D, Barlocco D, Toma L, Han DC, Kwon BM, Ogo N, Asai A, Legnani L, Gelain A
  • Journal Title: Eur J Org Chem Volume: 22 Issue: 22 Pages: 4907-4912
  • DOI: 10.1002/ejoc.201500599
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] がんの免疫逃避機構を標的とする新しい抗がん剤の開発 (2015)
  • Author(s): 浅井章良
  • Journal Title: 化学工業 Volume: 66 Pages: 13-21
• [Journal Article] Effect of the STAT3 inhibitor STX-0119 on the proliferation of a temozolomide-resistant glioblastoma cell line (2014)
  • Author(s): Ashizawa T, Akiyama Y, Miyata H, Iizuka A, Komiyama M, Kume A, Omiya M, Sugino T, Asai A, Hayashi N, Mitsuya K, Nakasu Y, Yamaguchi K
  • Journal Title: Int J Oncol. Volume: 411-8 Issue: 1 Pages: 411-418
  • DOI: 10.3892/ijo.2014.2439
  • Peer Reviewed
• [Journal Article] Modeling, synthesis and NMR characterization of novel chimera compounds targeting STAT3 (2014)
  • Author(s): Silvia Dell'Orto, Daniela Masciocchi, Stefania Villa, Fiorella Meneghetti, Giuseppe Celentano, Daniela Barlocco, Diego Colombo, Laura Legnani, Lucio Toma, Yoon Jung Jeon, Byoung-Mog Kwon, Akira Asai, Arianna Gelain
  • Journal Title: Med. Chem. Commun. Volume: ５ Issue: 11 Pages: 1651-1657
  • DOI: 10.1039/c4md00177j
  • Peer Reviewed
• [Presentation] テモゾロミド耐性神経膠芽腫細胞に対するSTAT3阻害剤とmTOR阻害剤との併用抗腫瘍効果 (2017)
  • Author(s): 芦澤忠、飯塚明、浅井章良、山口建、秋山康人
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2017-10-06
• [Presentation] ビスベンゾキノン誘導体によるSTAT3阻害作用の生化学的解析 (2016)
  • Author(s): 小跡竜也, 小郷尚久, 田口今日子, 増田吉昭, 浅井章良
  • Organizer: 日本薬学会第136年会
  • Place of Presentation: 横浜
  • Year and Date: 2016-03-27
• [Presentation] Cyclisation of Benzylisothiourea Provided Kynurenine Production Inhibitor without Indoleamine 2,3-Dioxygenase Inhibition (2015)
  • Author(s): Fukuda M, Miyachi H, Waki M, Asai A, Takikawa O, Matsuno K
  • Organizer: EFMC-ASMC'15 6th EFMC International Symposium on Advances in Synthetic and Medicinal Chemistry
  • Place of Presentation: Rehovot
  • Year and Date: 2015-11-15
  • Int'l Joint Research
• [Presentation] IDOを標的とした新規免疫調節化合物の合成と構造活性相関 (2015)
  • Author(s): 渡部美都、小郷尚久、高井一成、太田克美、松野研司、滝川修、浅井章良
  • Organizer: 第20回静岡健康・長寿学術フォーラム
  • Place of Presentation: 静岡
  • Year and Date: 2015-10-30
• [Presentation] 神経膠芽腫におけるTDO発現制御シグナルの解析 (2015)
  • Author(s): 池田智則、海野雄加、小郷尚久、浅井章良
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-10-08
• [Presentation] 恒常的にIDO1を発現するヒトがん細胞株の同定と解析 (2015)
  • Author(s): 福地壮吾、池田智則、海野雄加、小郷尚久、浅井章良
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-10-08
• [Presentation] テモゾロミド耐性神経膠芽細胞腫に対するSTAT3阻害剤STX-0119のin vitro及びin vivo抗腫瘍効果 (2014)
  • Author(s): 芦澤忠、飯塚明、小宮山優、浅井章良、山口建、秋山靖人
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Blocking STAT3 signaling in cancer: Synthesis of new potential inhibitors bearing the pyridazinone moiety (2014)
  • Author(s): FiorellaI Meneghetti, Silvia Dell'orto, Stefania Villa, Daniela Masclocchi, Ariana Gelain, Daniela Barlocco, Laura Legnani, Byoung-Mog Kwon, Akira Asai
  • Organizer: EFMC-ISMC 2014
  • Place of Presentation: Lisbon
  • Year and Date: 2014-09-07 – 2014-09-11
• [Presentation] Novel STAT3 inhibitors: Development of 1,2,5-oxadiazoles for anticancer therapy (2014)
  • Author(s): Federica Porta, Arianna Gelain, Daniela Masciocchi, Fiorella Meneghetti, Daniela Barlocco, Nicola Ferri, B-M Kwon, Akira Asai and Stefania Villa
  • Organizer: EFMC-ISMC 2014
  • Place of Presentation: Lisbon
  • Year and Date: 2014-09-07 – 2014-09-11
• [Presentation] 静岡県におけるアカデミア創薬の実践 (2014)
  • Author(s): 浅井章良
  • Organizer: 創薬懇話会2014
  • Place of Presentation: 岐阜
  • Year and Date: 2014-07-09 – 2014-07-10
  • Invited
• [Remarks] 創薬探索センター
  • URL: http://w3pharm.u-shizuoka-ken.ac.jp/tansaku/
• [Remarks]
  • URL: http://w3pharm.u-shizuoka-ken.ac.jp/tansaku/J%20Res.html
• [Remarks] CURRENT RESEARCH PROJECTS
  • URL: http://w3pharm.u-shizuoka-ken.ac.jp/tansaku/J%20Res.html