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

• 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
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥44,720,000 (Direct Cost: ¥34,400,000、Indirect Cost: ¥10,320,000); Fiscal Year 2020: ¥8,580,000 (Direct Cost: ¥6,600,000、Indirect Cost: ¥1,980,000); Fiscal Year 2019: ¥17,160,000 (Direct Cost: ¥13,200,000、Indirect Cost: ¥3,960,000); Fiscal Year 2018: ¥18,980,000 (Direct Cost: ¥14,600,000、Indirect Cost: ¥4,380,000)
• Keywords: HFpEF / 肥大型心筋症 / cMLCK / ミオシン調節軽鎖キナーゼ / 心不全

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.

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。

Research Products

• [Journal Article] Non-Radioactive In Vitro Cardiac Myosin Light Chain Kinase Assays (2020)
  • Author(s): Kamikubo Kenta、Tsukamoto Osamu、Uyama-Saito Yuki、Oya Ryohei、Tsubota Tomoya、Fujino Noboru、Asano Yoshihiro、Kato Hisakazu、Matsuoka Ken、Takashima Seiji
  • Journal Title: Journal of Visualized Experiments Volume: 160 Issue: 160 Pages: 1-1
  • DOI: 10.3791/61168
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Direct Sarcomere Modulators Are Promising New Treatments for Cardiomyopathies. (2019)
  • Author(s): Tsukamoto O.
  • Journal Title: Int J Mol Sci. Volume: 21 Issue: 1 Pages: 226-226
  • DOI: 10.3390/ijms21010226
  • Peer Reviewed
• [Journal Article] 直接的サルコメア制御剤による新しい心不全治療薬の開発 (2019)
  • Author(s): 塚本蔵
  • Journal Title: 実験医学 Volume: 37 Pages: 143-149
• [Journal Article] 心臓病における創薬開発、新たな治療介入で疾患を克服する (2019)
  • Author(s): 山田憲明, 塚本蔵
  • Journal Title: 心臓 Volume: 51 Pages: 1252-1259
  • NAID: 130007980571
• [Journal Article] Impact of cardiac myosin light chain kinase gene mutation on development of dilated cardiomyopathy (2019)
  • Author(s): Hodatsu A, Fujino N, Uyama Y, Tsukamoto O, Imai-Okazaki A, Yamazaki S, Seguchi O, Konno T, Hayashi K, Kawashiri MA, Asano Y, Kitakaze M, Takashima S, Yamagishi M
  • Journal Title: ESC Heart Fail Volume: 6 Issue: 2 Pages: 06-415
  • DOI: 10.1002/ehf2.12410
  • Peer Reviewed / Open Access
• [Book] 循環器内科 (2020)
  • Author(s): 塚本蔵、斎藤侑希、藤野陽、高島成二、北風政史
  • Total Pages: 6
  • Publisher: 科学評論社