Development and clinical application of low molecular chemicals that modulate myosin light chain kinase for the treatment of heart failure with preserved ejection fraction

2020 Fiscal Year Final Research Report

• Project/Area Number: 18H04050
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Medium-sized Section 53:Organ-based internal medicine and related fields
• Research Institution: National Cardiovascular Center Research Institute
• Principal Investigator: Kitakaze Masafumi 国立研究開発法人国立循環器病研究センター, 病院, 客員研究員 (20294069)
• Co-Investigator(Kenkyū-buntansha): 塚本 蔵 大阪大学, 生命機能研究科, 准教授 (80589151) ; 高島 成二 大阪大学, 生命機能研究科, 教授 (90379272) ; 山崎 悟 国立研究開発法人国立循環器病研究センター, 研究所, 室長 (70348796)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: HFpEF / 肥大型心筋症 / cMLCK

Outline of Final Research Achievements

Direct inhibitors of sarcomere contraction are expected to be a valuable therapeutic approach for hypertrophic cardiomyopathy (HCM). The phosphorylation of myosin regulatory light chain by cardiac-specific myosin light chain kinase (cMLCK) is well-known as one of the most important physiological modulators for cardiac sarcomere contraction. Therefore, the current study is aimed to develop the cMLCK-specific allosteric inhibitor as a potential drug for the treatment of HCM. We have finished the high-throughput screening using small-molecule chemical compound libraries and our original cMLCK assay system. Also, we successfully obtained the X-ray crystal structure of the cMLCK and calmodulin complex, which can be used for the lead exploration. Furthermore, we have demonstrated that the cMLCK inhibition can effectively suppress the contractility of cardiac sarcomere in cultured cardiomyocytes and mice model of the hereditary cardiomyopathy.

Free Research Field

循環器内科

Academic Significance and Societal Importance of the Research Achievements

HFpEFをきたす代表的疾患である肥大型心筋症(HCM)は、その有病率が約500人に1名と頻度が高く、若年者の突然死や青壮年の重症心不全の原因となる難治性疾患である。これまでHCMに対する治療法はなかったが、サルコメアの収縮性抑制（cMLCK）という新しい視点からHCMの治療薬の開発を目指す本研究は、有効なHCM薬物療法の開発に繋がる可能性を秘めており、医学的、社会学的意義は大きい。さらに、cMLCK阻害剤開発の過程で実施したcMLCKのX線結晶構造解析では、cMLCKとcalmodulinの共結晶構造解析に世界で初めて成功しており、学術的にも大きな意義がある。