Therapeutic strategy based on the direct degradation of disease-related proteins

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K06570
• 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: The University of Tokyo
• Principal Investigator: Yachide Tomomi 東京大学, 定量生命科学研究所, 准教授 (20401284)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 核内受容体 / エピジェネティクス / 構造展開 / 構造活性相関 / タンパク質分解誘導 / エストロゲン受容体 / ブロモドメイン / 医薬品探索

Outline of Final Research Achievements

I carried out research on the development of novel pharmacological agents for the treatment of endocrine-resistant breast cancer, for which no clear therapeutic strategy has been established. As a result, I developed pharmaceutical lead compounds that directly degrades disease-related proteins. Specifically, I selected estrogen receptor, which has been reported to be involved in these diseases, and bromodomain (BRD), which is the epigenetic regulator and attracting attention as a candidate therapeutic target for cancer, and developed compounds that induce the degradation of these proteins (selective estrogen receptor down-regulators and BRD degradation inducers). By analyzing the mechanism of action of the discovered compounds and their effects on downstream signaling, I have developed them into compounds that can truly serve as pharmaceutical leads.

Free Research Field

医薬化学

Academic Significance and Societal Importance of the Research Achievements

乳がんは、食の欧米化や妊娠回数の減少（女性ホルモン暴露期間の延長）に伴い、増加傾向にある。一方、閉経後乳がんやトリプルネガティブ乳がんといった、ホルモン療法耐性乳がんの当該所望化合物の創製・治療戦略は未だ確立していない。タンパクの寿命を制御する医薬は新たな治療戦略として期待されているが、その医薬化学的・生化学的情報は欠如している上、ファーマコフォアも限定されている。このような背景より、従来のホルモン療法と概念を異にする治療戦略の確立が求められている。本研究により、ホルモン療法耐性乳がん治療薬創製を目指した今後の『戦略的な基礎創薬化学研究』に革新的な方向性と学術基盤を付与することが可能である。