Molecular therapeutics for imatinib-resistant Ph-positive leukemias with newly developed Bcr-Abl/Lyn tyrosine kinase inhibitor

• Project/Area Number: 18390283
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Hematology
• Research Institution: Kyoto University
• Principal Investigator: MAEKAWA Taira Kyoto University, 大学院・医学研究科, 教授 (80229286)
• Co-Investigator(Kenkyū-buntansha): KIMURA Shinya 京都大学, 大学院・医学研究科, 助教 (80359794) ; ASHIHARA Eishi 京都大学, 大学院・医学研究科, 助教 (70275197)
• Project Period (FY): 2006 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥16,970,000 (Direct Cost: ¥15,200,000、Indirect Cost: ¥1,770,000); Fiscal Year 2008: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2007: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2006: ¥9,300,000 (Direct Cost: ¥9,300,000)
• Keywords: 慢性骨髄性白血病 / イマチニブ / INNO-406 / パフェチニブ / 遺伝子変異 / BCR-ABL分子標的治療 / Imatinib / Bafetinib / 耐性 / BCR-ABL / 分子標的治療 / NS-187 / 中枢神経性白血病 / 点突然変異 / 破骨細胞 / Bcr-Abl / Lyn / イマチニブ耐性 / フィラデルフィア染色体 / 分子標的療法

Research Abstract

Ablキナーゼドメインに遺伝子変異を持つイマチニブ(IM)抵抗性慢性骨髄性白血病(CML)に奏効する純国産のBcr-Abl/Lyn阻害剤INNO-406(NS-187、Bafetinib)を開発した。BafetinibはAbl親和性がIMより25-55倍高く、IM耐性に関与するLynとBcr-Ablを阻害するユニークな作用を持つチロシンキナーゼ阻害剤である。臨床第I相試験で有効性を確認した。

Research Products

• [Journal Article] Dua I BCR-ABL/LYN tyrosine kinase inhibitor (2009)
  • Author(s): Takeuchi, M., Kimura, S., Ashihara, E., Maekawa, T
  • Journal Title: Drug of the Future INNO-406(in press)
• [Journal Article] Modes of cell death execution and autophagy by INNO-406, a Bcr-Abl kinase inhibitor, in Bcr-Abl-positive leukemias (2008)
  • Author(s): Kamitsuji, Y., Kuroda, J., Kimura, S., Toyokuni, S., Watanabe, K., Ashihara, E., Tanaka, H., Watanabe, M., Matsubara, H., Mizushima, Y., Hiraumi, Y., Kawata E., Yoshikawa, T., Maekawa, T., Nakahata, T., Adachi, S
  • Journal Title: Cell Death Diff 15(11) Pages: 1712-1722
• [Journal Article] Detection of the V617F mutation in JAK2 using a novel, fully automated (2008)
  • Author(s): Tanaka, R., Kuroda, J., Stevenson, I. Ashihara, E., Ishikawa, T., Taki, T. Kobayashi, Y., Kamitsuji, Y., Kawata, E., Takeuchi, M., Murotani, Y., Yokota, A., Hirai, M., Majima, S., Taniwaki, M. Maekawa, T., Kimura, S
  • Journal Title: SNP super-rapid detector. Leuk Res 32(9) Pages: 1462-1467
• [Journal Article] Overcoming imatinib resistance using Src inhibitor CGP76030 (2008)
  • Author(s): Morinaga, K., Yamauchi, T., Kimura, T. Maekawa, T., Ueda, T
  • Journal Title: Abl inhibitor nilotinib, and Abl/Lyn inhibitor INNO-406 in newly established K562 variants with BCR-ABL gene amplification. Int J Cancer 122(11) Pages: 2621-2627
• [Journal Article] Anti-myeloma effect of Homoharringtonine with concomitant targeting of multiple myeloma-promoting molecules Mcl-1, XIAP and b-catenin (2008)
  • Author(s): Kuroda, J., Kamitsuji, Y., Kimura, S., Ashihara, E., Nakagawa, Y., Kawata, E. Takeuchi, M., Murotani, Y., Yokota, A., Tanaka, R., Andreeff, M., Taniwaki, M., Maekawa, T.
  • Journal Title: Int J Hematol 87(5) Pages: 507-515
• [Journal Article] Comaprison of imatinib, dasatinib, nilotinib, and INNO-406 in imatinib-resistant cell lines (2008)
  • Author(s): Deguchi, Y., Kimura, S., Ashihara, E.,Niwa, T., Hodohara, K., Fujiyama, Y., Maekawa, T.
  • Journal Title: Leuk Res 32(6) Pages: 980-983
• [Journal Article] ABT-737 is a useful component of combinatory chemotherapies for chronic myelogenous leukaemias with diverse drug resistance mechanisms (2008)
  • Author(s): Kuroda, J., Kimura, S., Kamitsuji, Y., Yokota, A., Ashihara, E., Kawata, E., Takeuchi, M., Tanaka, R., Tanaka, H., Matsumoto, Y., Andreeff, M., Taniwaki, M., Maekawa, T.
  • Journal Title: Brit J Haematol 140(2) Pages: 181-190
• [Journal Article] ABT-737 is a useful component of combinatory chemotherapies for chronic myelogenous leukaemias with diverse drug resistance mechanisms. (2008)
  • Author(s): Kuroda J, et al.
  • Journal Title: Brit J Haematol 140 Pages: 181-190
  • Peer Reviewed
• [Journal Article] Comaprison of imatinib, dasatinib, nilotinib, and INNO-406 in imatinib-resistant cell lines. (2008)
  • Author(s): Deguchi Y, et al.
  • Journal Title: Leuk Res 32 Pages: 980-983
  • Peer Reviewed
• [Journal Article] Modes of cell death execution and autophagy by INNO-406, a Bcr-Abl kinase inhibitor, in Bcr-Abl-positive leukemias. (2008)
  • Author(s): Kamitsuji Y, et al.
  • Journal Title: Cell Death Diff 15 Pages: 1712-1722
  • Peer Reviewed
• [Journal Article] Comparison of imatinib, dasatinib, nilotinib and INNO-406 in imatinib-resistant cell lines (2008)
  • Author(s): Deguchi Y
  • Journal Title: Leukemia Research (印刷中)
  • Peer Reviewed
• [Journal Article] The Bcr-Abl tyrosine kinase inhibitor imatinib and promising new agents against Philadelphia chromosome positive leukemias (2007)
  • Author(s): Maekawa, T., Ashihara, E., Kimura, S.
  • Journal Title: Review. Int J Clin Oncol 12(5) Pages: 327-340
  • NAID: 10019800087
• [Journal Article] Dual molecular targeting by INNO-406, a second generation Bcr-Abl inhibitor, and ABT737, an inhibitor of anti-apoptotic Bcl-2 proteins against Bcr-Abl-positive leukemia (2007)
  • Author(s): Kuroda, J., Kimura, S., Strasser, A., Andreeff, M., O' Reilly, L.A., Ashihara, E., Kamitsuji, Y., Yokota, A., Kawata, E., Deguchi, Y., Takeuchi, M., Tabe, Y., Taniwaki, M., Maekawa, T.
  • Journal Title: Cell Death Diff 14(9) Pages: 1667-77
• [Journal Article] INNO-406, a novel BCR-ABL/Lyn dual tyrosine kinase inhibitor suppresses the growth of Ph^+ leukemia cells in the central nervous system and cyclosporine A augments its in vivo activity (2007)
  • Author(s): Yokota, A., Kimura, S., Masuda, S., Ashihara, E., Kuroda, J., Sato, K., Kamitsuji, Y., Kawata, E., Deguchi, Y., Urasaki, Y., Terui, Y., Ruthardt, M., Ueda, T., Hatake, K., Inui, K., and Maekawa, T.
  • Journal Title: Blood 109(1) Pages: 306-314
• [Journal Article] INNO-406, a novel BCR-ABL/Lyn dual tyrosine kinase inhibitor, suppresses the growth of Ph+leukemia cells in the central nervous system and cyclosporine A augments its in vivo activity. (2007)
  • Author(s): Yokota A
  • Journal Title: Blood 109 Pages: 306-314
  • Peer Reviewed
• [Journal Article] Apoptosis-based dual molecular targeting by INNO-406, a second generation Bcr-Abl inhibitor, and ABT-737, an inhibitor of anti-apoptotic Bcl-2 proteins, against Bcr-Abl-positive leukemia. (2007)
  • Author(s): Kuroda J
  • Journal Title: Cell Beath & Diffrentiation 14 Pages: 1667-1677
  • Peer Reviewed
• [Journal Article] INNO-406, a novel BCR-ABL/Lyn dual tyrosine kinase inhibitor, suppresses the growth of Ph^+ leukemia cells in the central nervous system and cyclosporine A augments its in vivo activity (2007)
  • Author(s): Yokota A, et al.
  • Journal Title: Blood 109・1 Pages: 306-314
• [Journal Article] Combined effects of a third-generation bisphosphonate, zoledronic acid with other anti-cancer agents against osteosarcoma (2007)
  • Author(s): Horie N, et al.
  • Journal Title: Brit J Cancer 96・2 Pages: 255-261
• [Journal Article] Anti-donor antibody in patients receiving ABO-identical and HLA-mismatched living donor liver transplants : effect on survival (2007)
  • Author(s): Ashihara E, et al.
  • Journal Title: Transplantation 83・4 Pages: 506-509
• [Journal Article] The third-generation bisphosphonates inhibit tumor proliferation and induce apoptosis in murine osteosarcoma in vitro (2007)
  • Author(s): Horie N, et al.
  • Journal Title: Cancer Letter (In press)
• [Journal Article] γ δ T cells kill myeloma cells by sensing mevalonate metabolites and ICAM-1 molecules on cell surface (2007)
  • Author(s): Uchida R, et al.
  • Journal Title: Biochem Biophys Res Commun (In press)
• [Journal Article] Small interfering RNA targeting PLK-1 induces the apoptosis of synoviocytes of rheumatoid arthritis (2007)
  • Author(s): Wada M, et al.
  • Journal Title: Biochem Biophys Res Commun (In press)
• [Journal Article] Development of NS-187, a potent and selective dual Bcr-Abl/Lyn tyrosine kinase inhibitor (2006)
  • Author(s): Kimura, S., Niwa, T., Hirabayashi, K., Maekawa, T.
  • Journal Title: Cancer Chemo Pharmacol 58 Suppl 7 Pages: 55-61
• [Journal Article] In vivo inhibitory effect of NS-187, a dual Bcr-Abl/Lyn tyrosine kinase inhibitor, on the proliferation of leukemic cells harbour ing Abl kinase domain mutations (2006)
  • Author(s): Naito, H., Kimura, S., Nakaya, Y., Naruoka, H., Kimura, S., Ito, S., Wakayama, T., Maekawa, T. and Hirabayashi, K.
  • Journal Title: Leuk Res 30(11) Pages: 1443-1446
• [Journal Article] New tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia(review) (2006)
  • Author(s): Kimura, S., Ashihara, E., Maekawa, T.
  • Journal Title: Curr Pharma. Biotech 7(5) Pages: 371-379
• [Journal Article] In vivo inhibitory effect of NS-187, a dual Bcr-Abl/Lyn tyrosine kinase inhibitor, on the proliferation of leukemic cells harbouring Abl kinase domain mutations (2006)
  • Author(s): Naito, H., Kimura, S., Nakaya, Y., Naruoka, H., Ito, S., Wakayama, T., Maekawa, T. and Hirabayashi, K.
  • Journal Title: Leuk Res 30(11) Pages: 1443-1446
• [Journal Article] Development of NS-187, a potent and selective dual Bcr-Abl/Lyn tyrosine kinase inhibitor (2006)
  • Author(s): Kimura S, et al.
  • Journal Title: Cancer Chemo Pharmacol 58・Suppl 7 Pages: 55-61
• [Journal Article] New tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia (2006)
  • Author(s): Kimura S, et al.
  • Journal Title: Curr Pharma. Biotech 7・5 Pages: 371-379
• [Journal Article] In vivo inhibitory effect of NS-187, a dual Bcr-Abl/Lyn tyrosine kinase inhibitor, on the proliferation of leukemic cells harbouring Abl kinase domain mutations (2006)
  • Author(s): Naito H, et al.
  • Journal Title: Leuk Res 30・11 Pages: 1443-1446
• [Journal Article] A third generation bisphosphonate, minodronic acid (YM529), successfully prevented the growth of bladder cancer in vitro and in vivo (2006)
  • Author(s): Sato K et al.
  • Journal Title: Brit J Cancer 95・10 Pages: 1354-1361
• [Journal Article] Successful islet transplantation from non-heart-beating donor pancreata using modified Ricordi islet isolation method (2006)
  • Author(s): Matsumoto S, et al.
  • Journal Title: Transplantation 82・4 Pages: 460-465
• [Journal Article] How to comply with cGMP during early phase of translational cell therapy at academia (2006)
  • Author(s): Maekawa T
  • Journal Title: Clin Eval 33・3 Pages: 569-578
• [Presentation] On the cutting edge of cellular and molecular therapeutics developed in Kyoto university hospital (2008)
  • Author(s): Maekawa, T.
  • Organizer: The Annual Symposiurn 2008 of the Korean Society for Laboratory Medicine(Invited Plenary Lecture)
  • Place of Presentation: W Seoul-Wakerhill Hotel, Seoul, Korea
  • Year and Date: 2008-04-10
• [Presentation] On the cutting edge of cellular and molecular therapeutics developed in Kyoto university hospital. (2008)
  • Author(s): Maekawa T
  • Organizer: The Annual Symposium 2008 of the Korean Society for Laboratory Medicin e (Invited Plenary Lecture)
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2008-04-10
• [Presentation] Glyoxalase-I Is a Potential Therapeutic Target for Chronic Myelogenous Leukemia Cells That Have Acquired Drug Resistance through Adaptation to Hypoxia (2007)
  • Author(s): Takeuchi M, Kuroda J, Kimura S, Ashihara E, Umezawa K, Yasui E, Kawatani M, Osada H, Hodohara K, Fujiyama Y, Maekawa T
  • Organizer: The American Society of Hematology 49th Annual Meeting and Exposition(ASH)
  • Place of Presentation: Georgia World Congress Center, Atlanta, Georgia, USA((Abstract #2931) Blood, 110:11(supple))(2007)
  • Year and Date: 2007-12-10
• [Presentation] Bcr-Abl mutations and new agents in the treatment of imatinib-resistant Ph^+ leukemias (2007)
  • Author(s): Maekawa, T.
  • Organizer: The 12th Japanese Foundation for Cancer Research-International Symposium on Cancer Chemotherapy(JFCR-ISCC)
  • Place of Presentation: Tokyo, Japan
  • Year and Date: 2007-12-03
• [Presentation] Bcr-Abl mutations and new agents in the treatment of imatinib-resistant Ph+leukemias. (2007)
  • Author(s): Maekawa T
  • Organizer: The 12th Japanese Foundation for Cancer Research-International Symposium on Cancer Chemotherapy
  • Place of Presentation: Tokyo,Japan
  • Year and Date: 2007-12-03
• [Presentation] Cyclosporin A, a P-gp inhibitor, augments the anti-central nervous system Ph+ leukemia effects of INNO-406 (2006)
  • Author(s): Yokota, A., Kimura, S., Masuda, S., Ashihara, E., Urasaki, Y., Terui, Y., Ruthardt, M., Ueda, T., Hatake, K., Inui, K., Maekawa, T.
  • Organizer: The American Society of Hematology 48th Annual Meeting and Exposition(ASH)
  • Place of Presentation: Orange County Convention Center, Orlando, Frorida, USA(198)((Abstract#834)Blood108:11(supple))
  • Year and Date: 2006-12-12
• [Presentation] Novel dual Bcr-Abl/Lyn tyrosine kinase inhibitor for imatinib-resistant leukemia (2006)
  • Author(s): Maekawa, T.
  • Organizer: Seoul National University(Seoul, Korea)
  • Place of Presentation: Seoul National University(Seoul, Korea)
  • Year and Date: 2006-06-07
• [Book] がんの分子標的治療(鶴尾隆)(編集)(シグナル伝達系阻害剤) (2008)
  • Author(s): 前川平、芦原英司、木村晋也
  • Publisher: 南山堂、東京
• [Book] がんの分子標的治療 (2008)
  • Author(s): 前川平, ほか
  • Total Pages: 441
  • Publisher: 南山堂
• [Book] EBM-血液疾患の治療 (2007)
  • Author(s): 前川 平
  • Total Pages: 6
  • Publisher: 中外医学社
• [Book] Bone Marrow Transplantation : New Research(ed. By Davidson DF)(Stem cell transplantation for Ph+ leukemias in the imatinib and post-imatinib eras. In) (2006)
  • Author(s): Kimura, S., Maekawa, T.
  • Publisher: Nova Science Publishers, Inc. reviewNova Science Publishers, Inc. review
• [Book] イマチニブ以後の白血病に対する分子標的療法薬(高久史磨、溝口秀昭、坂田洋一、金倉譲、小島勢二)(編集)(Annual Review血液2006) (2006)
  • Author(s): 木村晋也、前川平
• [Book] Stem cell transplantation for Ph+ leukemias in the imatinib and post-imatinib eras. In, "Bone Marrow Transplantation : New Research." (2006)
  • Author(s): Kimura S, et al.
  • Total Pages: 165
  • Publisher: Nova Science Publishers, Inc.
• [Remarks] 脳の白血病に効果-新薬候補物質、少量で(日本経済新聞、2007年7月2日)
• [Remarks] がんナビ : 白血病対象INNO-406のフェーズ1が終了、予備的分析で好結果
  • URL: http://cancernavi.nikkeibp.co.jp/news/inno4061.html
• [Remarks] INNO-406 Demonstrates Positive Clinical Responses In Phase 1 Trial In Patients With Chronic Myeloid Leukemia
  • URL: http://www.medicalnewstoday.com/articles/129240.php
• [Remarks] INNO-406-Wikipedia
  • URL: http://de.wikipedia.org/wiki/INNO-406
• [Remarks]
  • URL: http://www.kuhp.kyoto-u.ac.jp/~dtm/
• [Remarks]
  • URL: http://www.kuhp.kyoto-u.ac.jp/~rccmt/
• [Remarks]
  • URL: http://www.icems.kyoto-u.ac.jp/cira/
• [Remarks]
  • URL: http://www.med.kyoto-u.ac.jp/GCOE/J/index.Html
• [Remarks]
  • URL: http://www.kuhp.kyoto-u.ac.jp/%7Edtm/index.html
• [Remarks]
  • URL: http://www.kuhp.kyoto-u.ac.jp/~dtm/
• [Patent(Industrial Property Rights)] 新規ユビキリン結合性小分子 (2007)
  • Inventor(s): 前川 平
  • Industrial Property Rights Holder: 京大TLO
  • Industrial Property Number: 2007-287570
  • Filing Date: 2007-11-05
• [Patent(Industrial Property Rights)] 変異の検出方法 (2006)
  • Inventor(s): 木村晋也、前川平、平井光春、間嶋智史
  • Industrial Property Rights Holder: 京都大学、アークレイ株式会社
  • Filing Date: 2006-08-08
• [Patent(Industrial Property Rights)] 変異の検出方法 (2006)
  • Inventor(s): 前川 平 ほか
  • Industrial Property Rights Holder: 前川 平 ほか
  • Industrial Property Number: 2006-216194
  • Filing Date: 2006-08-08