Drug Discovery Targeting Mitochondrial Iron Sulfur Protein MiNT, a Novel Molecular Target for Anti-Mitochondrial Therapy

2023 Fiscal Year Final Research Report

• Project/Area Number: 22K19383
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 47:Pharmaceutical sciences and related fields
• Research Institution: Gifu Pharmaceutical University
• Principal Investigator: Hideko Nagasawa 岐阜薬科大学, 薬学部, 教授 (90207994)
• Co-Investigator(Kenkyū-buntansha): 平山 祐 岐阜薬科大学, 薬学部, 准教授 (10600207) ; 辻 美恵子 岐阜薬科大学, 薬学部, 助教 (40709721)
• Project Period (FY): 2022-06-30 – 2024-03-31
• Keywords: ミトコンドリア / 鉄代謝 / 酸化ストレス / がん治療 / 鉄・ROS中毒 / MiNT

Outline of Final Research Achievements

The CISD3 gene, known to be highly expressed in various cancers, encodes the iron-sulphur protein MiNT, which localises to the mitochondrial matrix and is involved in intracellular iron, Fe-S and ROS homeostasis. Therefore, we aimed to develop ferroptosis inducers or inhibitors targeting MiNT. 1) Various TZD derivatives, including novel compounds, were designed and synthesised, but none showed significant ferroptosisu inducing activity. Interestingly, compounds showing intracellular iron divalent inducibility were found. 2) The ferroptosis inducer artesunate (ATS), whose activity is enhanced by mitochondrial targeting, was investigated for induction of ferroptosis in refractory cervical cancer and was found to induce heme-dependent cell death.

Free Research Field

創薬化学、ケミカルバイオロジー

Academic Significance and Societal Importance of the Research Achievements

「鉄・ROS中毒」表現型は悪性形質やがん幹細胞の特性であることをふまえれば、MiNT標的薬はがん細胞特異的にROSバーストを引き起こして悪性がん細胞を駆逐することができるものと期待される。このような創薬研究は、これまでに例がないことから、ミトコンドリア機能不全を有する難治性がん治療の有望な治療薬として期待できる。