The development of a novel therapeutic agent targeting MMSET histone methyltransferase in multiple myeloma

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K08740
• 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: Jichi Medical University
• Principal Investigator: Furukawa Yusuke 自治医科大学, 医学部, 教授 (00199431)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 多発性骨髄腫 / ハイリスク染色体異常 / 分子標的療法 / エピジェネティクス

Outline of Final Research Achievements

The prognosis of multiple myeloma (MM) has continuously improved via development of a series of novel molecular targeted drugs; however, the prognosis is still poor in cases with high-risk cytogenetic abnormalities (HRCA). Among HRCA, t(4;14) is the second most common abnormality with the prevalence of 15% in newly-diagnosed MM patients. MM cells carrying t(4;14) gain the resistance to several anti-MM drugs through the high expression of MMSET histone methyltransferase. We performed high-throughput screening in RIKEN small molecular compound libraries and identified RK-0800552 as a first-in class MMSET inhibitor. RK-0800552 exerted selective cytotoxicity against t(4;14)-positive MM cells in vitro and in vivo and showed a synergistic effect with pomalidomide in vitro and prolonged the survival of recipient mice in a murine t(4;14)-positive MM model without obvious side effects. RK-0800552 may be a candidate for a novel therapeutic agent for high-risk MM patient with t(4;14).

Free Research Field

血液内科学

Academic Significance and Societal Importance of the Research Achievements

MMSETを強発現する多発性骨髄腫は治療抵抗性で、治療成績の改善にはMMSETを特異的標的とする新薬の開発が必須と考えられる。しかしながらMMSETを特異的に阻害する薬剤については、現在のところ基礎研究レベルでもほとんど報告がなく、本研究は非常に高いプライオリティと臨床的意義を有する。今後、安全性試験と薬物動態試験を実施して前臨床POCを取得し、GMP基準での化合物の製造に関する具体的方針を固め、製薬企業とタイ・アップして臨床治験へ展開することが可能なレベルにスキップ・アップしたい。