Drug discovery targeted against RSK2 in multiple myeloma

• Project/Area Number: 19K08872
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: JUNYA KURODA 京都府立医科大学, 医学(系)研究科(研究院), 教授 (70433258)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 多発性骨髄腫 / RSK2 / AKT / 分子標的 / 創薬 / 小分子化合物 / BH3-only protein / Bid / 創薬研究

Outline of Research at the Start

研究代表者は、先行研究により、難治性造血器悪性腫瘍であり、細胞遺伝学的・分子生物学的異常が複雑、かつ、症例間で分子異常のパターンが高度に不均一なMMにおいて、RAS経路最後尾のシグナル媒介分子であるRSK2が、上流分子の構造的異常や活性の状態に関わらず普遍的・恒常的に活性化状態にあり、病態形成において中心的役割を果たすこと、その阻害は分子生物学的異常のタイプに関わらずRAS経路シグナルを最後尾で遮断可能であり、治療標的分子となりうることを見出した。しかし、これまでにヒトに投与可能で特異性の高いRSK2標的薬は無いことから、本研究ではRSK2を標的とするヒット・リード化合物の開発に挑戦する。

Outline of Final Research Achievements

Multiple myeloma (MM) is cytogenetically and molecularly complex and heterogeneous and remains a difficult-to-treat hematologic malignancy with currently available therapeutics. Based on the previous studies suggesting the N-terminal kinase domain (NTKD) of RSK2, a serine-threonine kinase, as a novel potential therapeutic molecular target for MM, this study aimed the drug discovery of RSK2-NTKD-targeted therapeutic against MM. As the result, we in this study developed the therapeutic rationale for the simultaneous targeting of RSK2-NTKD/AKT/S6K for MM, as the combinatory blockade of those three molecules enables the blockade of several critical molecular pathways for MM pathophysiology. Then, we discovered several derivatives of 5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one as potential lead compounds for the simultaneous targeting of RSK2-NTKD/AKT/S6K in myeloma cells. We will further extend our research for drug development based on these results in the future.

Academic Significance and Societal Importance of the Research Achievements

本研究ではRSK2の機能をAKT, S6Kが補完すること、これらを同時に阻害することでMYCやMTOR、VEGF、各種の造腫瘍性サイトカインシグナルの同時ブロックが可能となり強力な抗腫瘍効果が得られることを見出した。これまでヒトに治療薬として投与可能なRSK2標的薬は臨床実装化されていないが、本研究においてRSK2/AKT/S6Kの同時制御を可能とするリード化合物として複数の5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one誘導体を同定したことは、今後の創薬開発にむけて重要な成果を得たものと考える。

Research Products

• [Journal Article] The Rationale for the Dual-Targeting Therapy for RSK2 and AKT in Multiple Myeloma. (2022)
  • Author(s): Isa R, Horinaka M, Tsukamoto T, Mizuhara K, Fujibayashi Y, Taminishi-Katsuragawa Y, Okamoto H, Yasuda S, Kawaji-Kanayama Y, Matsumura-Kimoto Y, Mizutani S, Shimura Y, Taniwaki M, Sakai T, Kuroda J.
  • Journal Title: Int J Mol Sci. Volume: 23 Issue: 6 Pages: 2919-2936
  • DOI: 10.3390/ijms23062919
  • Peer Reviewed / Open Access
• [Journal Article] Expression of activated B cell gene signature is predictive of the outcome of follicular lymphoma. (2022)
  • Author(s): Tsukamoto T, Tokuda Y, Nakano M, Tashiro K, Kuroda J.
  • Journal Title: Blood Adv Volume: 6 Issue: 6 Pages: 1932-1936
  • DOI: 10.1182/bloodadvances.2021005876
  • Peer Reviewed / Open Access
• [Journal Article] Detection of novel and recurrent conjoined genes in non-Hodgkin B-cell lymphoma (2021)
  • Author(s): Matsumoto Y, Tsukamoto T, Chinen Y, Shimura Y, Sasaki N, Nagoshi H, Sato R, Adachi H, Nakano M, Horiike S, Kuroda J, Taki T, Tashiro K, Taniwaki M.
  • Journal Title: Journal of Clinical and Experimental Hematopathology Volume: 61 Issue: 2 Pages: 71-77
  • DOI: 10.3960/jslrt.20033
  • NAID: 130008049325
  • ISSN: 1346-4280, 1880-9952
  • Peer Reviewed
• [Journal Article] EWSR1 overexpression is a pro-oncogenic event in multiple myeloma (2021)
  • Author(s): Nishiyama D, Chinen Y, Isa R, Fujibayashi Y, Kuwahara-Ota S, Yamaguchi J, Takimoto-Shimomura T, Matsumura-Kimoto Y, Tsukamoto T, Shimura Y, Kobayashi T, Horiike S, Taniwaki M, Handa H, Kuroda J.
  • Journal Title: Int J Hematol Volume: 113 Issue: 3 Pages: 381-394
  • DOI: 10.1007/s12185-020-03027-0
  • Peer Reviewed / Open Access
• [Journal Article] Aberrant BUB1 Overexpression Promotes Mitotic Segregation Errors and Chromosomal Instability in Multiple Myeloma (2020)
  • Author(s): Fujibayashi Y, Isa R, Nishiyama D, Sakamoto-Inada N, Kawasumi N, Yamaguchi J, Kuwahara-Ota S, Matsumura-Kimoto Y, Tsukamoto T, Chinen Y, Shimura Y, Kobayashi T, Horiike S, Taniwaki M, Handa H, Kuroda J
  • Journal Title: Cancers Volume: 12 Issue: 8 Pages: 2206-2206
  • DOI: 10.3390/cancers12082206
  • Peer Reviewed / Open Access
• [Journal Article] Toward further simplification of elotuzumab therapy by subcutaneous administration (2020)
  • Author(s): Shimura Y, Tsukamoto T, Yamaguchi J, Kuwahara-Ota S, Isa R, Nishiyama D, Kobayashi T, Horiike S, Suzuki A, Kuroda J
  • Journal Title: Int J Hematol Volume: 112 Issue: 3 Pages: 427-428
  • DOI: 10.1007/s12185-020-02942-6
  • Peer Reviewed / Open Access
• [Journal Article] Lenalidomide and pomalidomide potently interfere with induction of myeloid-derived suppressor cells in multiple myeloma (2020)
  • Author(s): Kuwahara-Ota S, Shimura Y, Steinebach C, Isa R, Yamaguchi J, Nishiyama D, Fujibayashi Y, Takimoto-Shimomura T, Mizuno Y, Matsumura-Kimoto Y, Tsukamoto T, Chinen Y, Kobayashi T, Horiike S, Taniwaki M, Gutschow M, Kuroda J
  • Journal Title: Br J Haematol Volume: 191 Issue: 5 Pages: 784-795
  • DOI: 10.1111/bjh.16881
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Serine-227 in the N-terminal kinase domain of RSK2 is a potential therapeutic target for mantle cell lymphoma (2020)
  • Author(s): Matsumura-Kimoto Y, Tsukamoto T, Shimura Y, Chinen Y, Tanba K, Kuwahara-Ota S, Fujibayashi Y, Nishiyama D, Isa R, Yamaguchi J, Kawaji-Kanayama Y, Kobayashi T, Horiike S, Taniwaki M, Kuroda J
  • Journal Title: Cancer Med Volume: 9 Issue: 14 Pages: 5185-5199
  • DOI: 10.1002/cam4.3136
  • Peer Reviewed / Open Access
• [Journal Article] Tumor-specific transcript variants of cyclin D1 in mantle cell lymphoma and multiple myeloma with chromosome 11q13 abnormalities (2020)
  • Author(s): Chinen Yoshiaki、Tsukamoto Taku、Maegawa-Matsui Saori、Matsumura-Kimoto Yayoi、Takimoto-Shimomura Tomoko、Tanba Kazuna、Mizuno Yoshimi、Fujibayashi Yuto、Kuwahara-Ota Saeko、Shimura Yuji、Kobayashi Tsutomu、Horiike Shigeo、Taniwaki Masafumi、Kuroda Junya
  • Journal Title: Experimental Hematology Volume: - Pages: 45-53.e1
  • DOI: 10.1016/j.exphem.2020.02.004
  • Peer Reviewed / Open Access
• [Presentation] 日常診療と形質細胞性腫瘍. (2021)
  • Author(s): 黒田純也
  • Organizer: 日本内科学会近畿地方会生涯教育講演.
  • Invited
• [Presentation] 多発性骨髄腫における分子腫瘍学的多様性の克服に向けて. (2021)
  • Author(s): 黒田純也
  • Organizer: 千里ライフサイエンスセミナー
  • Invited
• [Presentation] RSK2Ser227 in N-terminal kinase domain is a potential therapeutic target for mantle cell lymphoma (2020)
  • Author(s): Kimoto Y, Tsukamoto T, Shimura Y, Chinen Y, Tanba K, Ota S, Fujibayashi Y, Nishiyama D, Isa R, 1，Yamaguchi J, Kanayama Y, Kobayashi T, Horiike S, Taniwaki M, Kuroda J
  • Organizer: 第82回日本血液学会学術総会
• [Presentation] BUB1 overexpression may associate with karyotypic clonal evolution in multiple myeloma (2020)
  • Author(s): Fujibayashi Y, Inada N，Kawasumi N，Ota S, Isa R, Yamaguchi J, Nishiyama D, Kimoto Y, Chinen Y, Shimura Y, Kobayashi T, Taniwaki M, Kuroda J
  • Organizer: 第82回日本血液学会学術総会
• [Presentation] 多発性骨髄腫に対する分子標的治療戦略の理論とエビデンス (2020)
  • Author(s): 黒田純也
  • Organizer: 第58回日本癌治療学会学術集会
  • Invited
• [Presentation] Expression of activated B cell gene signature is predictive for prognosis in follicular lymphoma (2020)
  • Author(s): Tsukamoto T, Tokuda Y, Nakano N, Shimura Y, Kobayashi T, Horiike S, Tashiro K, Kuroda J
  • Organizer: 第82回日本血液学会学術総会
• [Presentation] Clinical and functional significance of EWSR1 overexpression in multiple myeloma (2020)
  • Author(s): Nishiyama D, Chinen Y, Fujibayashi Y, Isa R, Ota S, Kimoto Y, Yamaguchi J, Tsukamoto T, Shimura Y, Kobayashi T, Horiike S, Taniwaki M, Handa H, Kuroda J
  • Organizer: 第82回日本血液学会学術総会
• [Remarks] 京都府立医科大学大学院医学研究科先端医療・ゲノム医学分野 血液内科学
  • URL: http://www.kpum-hematology.net/study/study02.html
• [Remarks] 京都府立医科大学 血液内科学教室 研究「骨髄腫」
  • URL: http://www.f.kpu-m.ac.jp/k/hematol/study/study02.html