Drug discovery targeted against RSK2 in multiple myeloma

2021 Fiscal Year Final Research Report

• 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
• Keywords: 多発性骨髄腫 / RSK2 / AKT / 分子標的 / 創薬 / 小分子化合物

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.

Free Research Field

血液内科学

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。