Development of KLF5 inhibitors that selectively inhibit cancer and improve cardiac function and elucidation of their molecular mechanisms of action

2023 Fiscal Year Final Research Report

• Project/Area Number: 19K07512
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49030:Experimental pathology-related
• Research Institution: Jichi Medical University
• Principal Investigator: Nakaya Takeo 自治医科大学, 医学部, 准教授 (80512277)
• Co-Investigator(Kenkyū-buntansha): 永井 良三 自治医科大学, 医学部, 学長 (60207975) ; 相澤 健一 自治医科大学, 医学部, 准教授 (70436484)
• Project Period (FY): 2019-04-01 – 2024-03-31
• Keywords: KLF5 / 天然変性蛋白 / 分子標的薬 / がん分子創薬 / 核内因子

Outline of Final Research Achievements

Transcription factor KLF5 is a therapeutic target for colorectal cancer, heart failure, and other diseases. However, it has been difficult to create molecular-targeted drugs because the steric structure of KLF5 has not been elucidated. We have developed a small molecule compound that mimics the α-helix structure of the induced helical motif, which is the site of protein-protein interaction and is predicted from the amino acid sequence. This compound inhibits the formation of a protein complex between KLF5 protein and its deubiquitinating enzyme USP3, thereby reducing the amount of KLF5 protein. It also inhibits and kills colon cancer cells without damaging normal cells, and suppresses tumors of transplanted colon cancer cells in mice with minimal side effects. The efficacy of the drug for heart failure is currently under study.

Free Research Field

病理学、がん治療開発

Academic Significance and Societal Importance of the Research Achievements

がん原因因子、心疾患を悪化させる因子の多くが立体構造を解明できない天然変性蛋白、あるいは標的薬が核膜と細胞膜の両方を通過する低分子薬でなければならない核内因子である。このためがんゲノム解析等でがん原因因子の同定が進む中、その結果が必ずしも進行がん患者に適した分子標的薬の提供、予後改善に結び付いていない。本研究成果は、今まで創薬困難であった、多くの天然変性蛋白や核内因子を標的に、副作用少なく効果の高い分子標的薬を創製する方法の開発につながると期待される。