Development of Novel Cell Regulation Technology targeting Nuclear Receptors

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K06572
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47010:Pharmaceutical chemistry and drug development sciences-related
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Yuasa Mari 東京医科歯科大学, 生体材料工学研究所, 助教 (80506303)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 核内受容体

Outline of Final Research Achievements

We investigated the effects of synthetic retinoid Am80 in combination with epigenetic inhibitors in various cancer cells. Histone deacetylation inhibitors belonging to Class IIb were effective in combination with Am80. This suggests that HSP90, one of the targets of HDAC6 in Class IIb showing affinity as a chaperone of RARα, is hyperacetylated and dissociates from RARα, thereby regulating nuclear translocation. Furthermore, we investigated whether the nuclear migration of RARα is commonly regulated in cell types other than solid tumors and in culture conditions such as aggregation and spheroid. We found that the combined effects of the two drugs and the regulation of RAR nuclear migration are more pronounced under some conditions than in normal two-dimensional culture.

Free Research Field

創薬化学

Academic Significance and Societal Importance of the Research Achievements

核内受容体をターゲットとした創薬の成功例として、急性前骨髄急性白血病APLの治療薬Am80をはじめ、エストロゲンレセプター（ER）をターゲットとした乳がん治療薬タモキシフェン、ペルオキシソーム増殖因子活性化受容体γ（PPARγ）をターゲットとした2型糖尿病の治療薬ロシグリタゾンなどがある。しかしながら、疾患に関与する核内受容体の精緻な制御は未だ途上であり従来のアゴニスト・アンタゴニストによる制御に留まらない新しい概念が求められている。本研究成果は従来の核内受容体リガンドによる制御に留まらないユビキチン化などの分解制御や細胞内輸送の制御など、新しい核内受容体制御法の開発に貢献しうると考えられる。