Drug Discovery of Novel Small-Molecule Antagonists for Nr4a1

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K06574
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47040:Pharmacology-related
• Research Institution: University of Toyama
• Principal Investigator: Takasaki Ichiro 富山大学, 学術研究部工学系, 准教授 (00397176)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: Nr4a1 / 低分子拮抗薬 / 癌性疼痛 / 抗癌作用 / アロディニア

Outline of Final Research Achievements

In this study, to investigate whether the Nr4a1 small-molecule antagonist (Compound A) has both anticancer and analgesic effects, we evaluated it in a mouse model of cancer pain induced by transplantation of cancer cells into the femur. When Compound A was administered to this mouse model, both antitumor and analgesic effects were observed. However, the effects were partial, so we conducted synthetic research on more potent Nr4a1 small-molecule antagonists and succeeded in obtaining a new compound, A-15. Compound A-15 showed better antitumor and analgesic activity than compound A in a mouse model of cancer pain, suggesting that Nr4a1 antagonists may be compounds with both antitumor and analgesic activities.

Free Research Field

薬理学

Academic Significance and Societal Importance of the Research Achievements

既存の抗癌薬には骨髄抑制や嘔吐，下痢などの強い副作用が伴う。また癌患者の70％近くが経験する癌性疼痛に対して使用されるオピオイド鎮痛薬にも，呼吸抑制や嘔吐，便秘など副作用が伴う。したがって，一つの薬で癌も痛みも抑え，かつ従来の抗癌薬・鎮痛薬の副作用を回避できる薬が開発できれば，癌や癌性疼痛，薬の副作用に苦しむ患者を救う画期的な治療薬となる可能性がある。本研究で開発した新規Nr4a1拮抗薬は，骨癌性疼痛モデルマウスにおいて抗癌作用と鎮痛作用を併せ持つことが明らかとなった。癌と癌の痛みに苦しむ患者にとって新たな治療の選択肢となるかもしれない。