Protein complex analysis of transcriptional factor KLF, and development of a low molecular weight compound that inhibits KLF5 transcriptional activity.

2017 Fiscal Year Final Research Report

• Project/Area Number: 15H04824
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: Jichi Medical University
• Principal Investigator: Nagai Ryozo 自治医科大学, 医学部, 学長 (60207975)
• Co-Investigator(Kenkyū-buntansha): 相澤 健一 自治医科大学, 医学部, 准教授 (70436484) ; 仲矢 丈雄 自治医科大学, 医学部, 講師 (80512277)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Keywords: KLF5 / 蛋白間相互作用阻害薬 / 分子創薬 / 心不全 / 癌

Outline of Final Research Achievements

From our previous studies, KLF5 is a potential therapeutic target for cardiovascular disease and cancer. However, structure-based drug design of KLF5 inhibitors has not been successful because KLF5 is an intrinsically disordered protein. Therefore, we have analyzed the structure of KLF5 in silico and synthesized several low molecular weight compounds which mimic the a-helical region of KLF5 which is suggested to be involved in protein-protein interactions. We have found several compounds to inhibit KLF5 function as shown by inhibition of cell growth of smooth muscle cells and colorectal cancer cells. The compounds were found to reduce protein levels of KLF5 without altering KLF5 mRNA levels, suggesting degradation of KLF5 was accelerated in the presence of the compounds. We further found that the compounds can improve heart failure caused by aortic constriction. We conclude these compounds to be promising new therapeutic drugs for cardiovascular diseases as well as cancers.

Free Research Field

循環器内科学