Citation: Anqi Shi, Jiahao Xiang, Qingyun Zhang, Minghui Tan, Wen Xiao, Yang Yang, Lin Zhao, Jian Liu, An Pan, Junwei Wang, Lihong Hu. Discovery of a novel cardiac myosin inhibitor for the treatment of hypertrophic cardiomyopathy[J]. Chinese Chemical Letters, ;2026, 37(8): 111786. doi: 10.1016/j.cclet.2025.111786 shu

Discovery of a novel cardiac myosin inhibitor for the treatment of hypertrophic cardiomyopathy

Jiangsu Key Laboratory for Functional Substance of Chinese Medicine, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China

panan@njucm.edu.cn

jwwang@njucm.edu.cn

lhhu@njucm.edu.cn

Received Date: 1 July 2025
Revised Date: 3 September 2025
Accepted Date: 4 September 2025
Available Online: 5 September 2025

Figures(4)

Inhibiting the contraction of cardiac myosin is an important strategy for treating hypertrophic cardiomyopathy (HCM). However, currently only MYK-461 has been approved for market, and its safety and pharmacokinetic (PK) properties still have deficiencies. Herein, we reported the discovery of a novel and potent cardiac myosin inhibitor Z5–11 through rational structural optimization of MYK-461. Compared with MYK-461, Z5–11 exhibited stronger inhibitory activity against myosin ATPase and could significantly inhibit myocardial cell contraction, as well as alleviate Ang Ⅱ-induced cardiac hypertrophy. The cytotoxicity assessment on rat myocardial cells showed that Z5–11 exhibited better safety than MYK-461. The PK study revealed that Z5–11 had reasonable half-life time (t_1/2 = 2.74 h), and excellent oral bioavailability (F = 105.2%). More importantly, Z5–11 can effectively ameliorate transverse aortic constriction (TAC)-induced cardiac dysfunction and cardiac hypertrophy and remodeling in mice. These findings suggest that Z5–11 can be developed as a promising drug candidate for treating HCM.
- Hypertrophic cardiomyopathy,
- Cardiac myosin inhibitor,
- Safety,
- Pharmacokinetic properties,
- Structural optimization
1. [1]
  C.W. Tsao, A.W. Aday, Z.I. Almarzooq, et al., Circulation 145 (2022) e153–e639.
2. [2]
  G.G. Schiattarella, J.A. Hill, Circulation 131 (2015) 1435–1447. doi: 10.1161/CIRCULATIONAHA.115.013894
3. [3]
  W.X. Wu, B.B. Wang, Y. Qin, et al., Chin. Chem. Lett. 36 (2025) 110584. doi: 10.1016/j.cclet.2024.110584
4. [4]
  B.J. Maron, E.J. Rowin, M.S. Maron, JACC Heart Fail. 6 (2018) 376–378. doi: 10.1016/j.jchf.2018.03.004
5. [5]
  S.R. Ommen, S. Mital, M.A. Burke, et al., Circulation 142 (2020) e533–e557.
6. [6]
  Y.K. Tham, B.C. Bernardo, J.Y. Ooi, K.L. Weeks, J.R. McMullen, Arch. Toxicol. 89 (2015) 1401–1438. doi: 10.1007/s00204-015-1477-x
7. [7]
  A. Jaiswal, V.Q. Nguyen, B.J. Carry, T.H. le Jemtel, J. Card. Fail. 22 (2016) 829–839. doi: 10.1016/j.cardfail.2016.03.017
8. [8]
  S.Y. Zhang, J. Geriatr. Cardiol. 22 (2025) 277–331. doi: 10.26599/1671-5411.2025.03.002
9. [9]
  B. Bozkurt, Nat. Rev. Cardiol. 21 (2024) 545–555. doi: 10.1038/s41569-024-00997-0
10. [10]
  H. Yuan, F. Zhang, H. Huang, et al., Chin. Chem. Lett. 36 (2025) 109965. doi: 10.1016/j.cclet.2024.109965
11. [11]
  G.A. Nichols, K. Reynolds, T.M. Kimes, A.G. Rosales, W.W. Chan, Am. J. Cardiol. 116 (2015) 1088–1092. doi: 10.1016/j.amjcard.2015.07.018
12. [12]
  H. Dokainish, K. Teo, J. Zhu, et al., Lancet Glob. Health. 5 (2017) e665–e672. doi: 10.1016/S2214-109X(17)30196-1
13. [13]
  O. Tsukamoto, Int. J. Mol. Sci. 21 (2020) 226–238.
14. [14]
  MyoKardia, a wholly owned subsidiary of Bristol Myers Squibb, https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/214998s000lbl.pdf, 2022.
15. [15]
  E. Braunwald, S. Saberi, T.P. Abraham, P.M. Elliott, I. Olivotto, Eur. Heart. J. 44 (2023) 4622–4633. doi: 10.1093/eurheartj/ehad637
16. [16]
  R.F. Kawas, R.L. Anderson, S.R.B. Ingle, et al., J. Biol. Chem. 292 (2017) 16571–16577. doi: 10.1074/jbc.M117.776815
17. [17]
  W. Ma, C.L. Del Rio, L. Qi, et al., Proc. Natl. Acad. Sci. U. S. A. 121 (2024) e2314914121. doi: 10.1073/pnas.2314914121
18. [18]
  N. Zatorski, E.A. Sobie, A. Schlessinger, Trends. Pharmacol. Sci. 44 (2023) 318–319. doi: 10.1016/j.tips.2023.02.005
19. [19]
  I. Olivotto, A. Oreziak, R. Barriales-Villa, et al., Lancet 396 (2020) 759–769. doi: 10.1016/S0140-6736(20)31792-X
20. [20]
  E.M. Green, H. Wakimoto, R.L. Anderson, et al., Science 351 (2016) 617–621. doi: 10.1126/science.aad3456
21. [21]
  S.J. Keam, Drugs 82 (2022) 1127–1135. doi: 10.1007/s40265-022-01739-7
22. [22]
  M.P. Grillo, J.C.L. Erve, R. Dick, et al., Xenobiotica 49 (2019) 718–733. doi: 10.1080/00498254.2018.1495856
23. [23]
  Y. Xu, L. Wang, L. Yang, et al., Chin. Chem. Lett. 36 (2025) 110958. doi: 10.1016/j.cclet.2025.110958
24. [24]
  X. Wu, N. Chen, P. Hsu, et al., Clin. Transl. Sci. 17 (2024) e13877. doi: 10.1111/cts.13877
25. [25]
  G. Kayki-Mutlu, Z.S. Aksoyalp, L. Wojnowski, M.C. Michel, Naunyn Schmiedebergs Arch. Pharmacol. 396 (2023) 1619–1632. doi: 10.1007/s00210-023-02465-x
26. [26]
  A. Humayra, C.S. Joseph, K. Mohsin, A.S. Rizwan, A. Majed, M. Nurunnabi, Chin. Chem. Lett. 33 (2022) 2773–2782. doi: 10.1016/j.cclet.2022.01.011
27. [27]
  F.I. Malik, L.A. Robertson, D.R. Armas, et al., JACC Basic Transl. Sci. 7 (2022) 763–775. doi: 10.1016/j.jacbts.2022.04.008
28. [28]
  S.J. Lehman, C. Crocini, L.A. Leinwand, Nat. Rev. Cardiol. 19 (2022) 353–363. doi: 10.1038/s41569-022-00682-0
29. [29]
  MyoKardia Programs MyoKardia, https://myokardia.com/programs, 2020 (accessed on 22 August 2020).
30. [30]
  AdisInsight. A phase 1 randomized, placebo-controlled, single and multiple-ascending dose study of myk-224 in healthy volunteers—AdisInsight. https://adisinsight.springer.com/trials/700301316 (accessed on 1 September 2020).
31. [31]
  M.S. Maron, A. Masri, M.E. Nassif, et al., N. Engl. J. Med. 390 (2024) 1849–1861. doi: 10.1056/nejmoa2401424
32. [32]
  C. Chuang, S. Collibee, L. Ashcraft, et al., J. Med. Chem. 64 (2021) 14142–14152. doi: 10.1021/acs.jmedchem.1c01290
33. [33]
  J.S. Allingham, R. Smith, I. Rayment, Nat. Struct. Mol. Biol. 12 (2005) 378–379. doi: 10.1038/nsmb908
34. [34]
  J.J. Frye, V.A. Klenchin, C.R. BagShaw, I. Rayment, Biochemistry 49 (2010) 4897–4907. doi: 10.1021/bi1001344
1. [1]
  Mei-Chen Liu , Qing-Song Liu , Yi-Zhou Quan , Jia-Ling Yu , Gang Wu , Xiu-Li Wang , Yu-Zhong Wang . Phosphorus-silicon-integrated electrolyte additive boosts cycling performance and safety of high-voltage lithium-ion batteries. Chinese Chemical Letters, 2024, 35(8): 109123-. doi: 10.1016/j.cclet.2023.109123
2. [2]
  Yi-You Huang , Xiang Luo , Kai Zhang , Yulan Liang , Furong Zhang , Guochao Liao , Shenghong Xie , Pei-Luo Huang , Siyu Hou , Qian Zhou , Yong Zou , Hai-Bin Luo . Structure-based optimization of isoaurostatin as novel PDE4 inhibitors with anti-fibrotic effects. Chinese Chemical Letters, 2025, 36(8): 110586-. doi: 10.1016/j.cclet.2024.110586
3. [3]
  Kai Tang , Guochao Wei , Peng Zhan . Breaking the impossible: The evolutionary journey of lenacapavir, a long-acting anti-HIV drug. Chinese Chemical Letters, 2025, 36(7): 110500-. doi: 10.1016/j.cclet.2024.110500
4. [4]
  Yi-Ru Bai , Qing-Chuan Duan , Dong-Jie Seng , Ying Xu , Hong-Bo Ren , Jie Zhang , Dan-Dan Shen , Li Yang , Hong-Min Liu , Shuo Yuan . A comprehensive review of small molecule drugs approved by the FDA in 2024: Advance and prospect. Chinese Chemical Letters, 2025, 36(10): 111025-. doi: 10.1016/j.cclet.2025.111025
5. [5]
  Wei Yan , Naizhen Zhang , Xiao Liu , Qiyu He , Xucheng Lv , Jianghui Sun , Lili Zhuang , Yuexin Zou , Yajie Zhang , Yuhang Liang , Yanjie Wang , Siyuan Li , Yonghui Sun . Development of visible-light photocaged molecular glues (vc-MGs) for B-cell malignancies therapy with improved safety and pharmacokinetic profiles in vivo. Chinese Chemical Letters, 2026, 37(5): 112064-. doi: 10.1016/j.cclet.2025.112064
6. [6]
  Gao-Sheng Zhu , Zhen-Hang Xu , Shao-Zhan Lan , Long Li , Yan-Ying Zheng , Lu Zhang , Qiao-Xia Shang , Bao-Yi Yu , Chong-Chen Wang . Sustainable fungicide delivery via imazalil-functionalized nano-coordination polymer carriers: Enhanced stability, environmental safety, and pH-responsive properties. Chinese Chemical Letters, 2026, 37(2): 111428-. doi: 10.1016/j.cclet.2025.111428
7. [7]
  Weiguang Zhao . 化学实验室常见安全事故应急处置的思考与建议. University Chemistry, 2025, 40(8): 291-297. doi: 10.12461/PKU.DXHX202410053
8. [8]
  Hua Yu , Dingdu Chen , Xuan Wang , Lijun Yang , Geming Wang , Pu Hu . MOF-encapsulated phosphorus/nitrogen ionic liquid as a multifunctional flame-retardant additive for high-safety lithium-ion batteries. Acta Physico-Chimica Sinica, 2026, 42(7): 100201-0. doi: 10.1016/j.actphy.2025.100201
9. [9]
  Xiao-Qian Wan , Ya-Ning Xu , Jian-Xin Yang , Dan Tian , Li-Long Dang , Feng Bai , Lu-Fang Ma . Structural optimization of organometallic cages for enhanced photothermal solar water evaporation. Chinese Journal of Structural Chemistry, 2025, 44(10): 100705-100705. doi: 10.1016/j.cjsc.2025.100705
10. [10]
  Jianmei Han , Peng Wang , Hua Zhang , Ning Song , Xuguang An , Baojuan Xi , Shenglin Xiong . Performance optimization of chalcogenide catalytic materials in lithium-sulfur batteries: Structural and electronic engineering. Chinese Chemical Letters, 2024, 35(7): 109543-. doi: 10.1016/j.cclet.2024.109543
11. [11]
  Ke-Lin Zhu , Zhi-Ao Li , Jiaqi Liang , Yong He , Han-Yuan Gong . Atropisomeric carbon-rich macrocycles: Synthesis, structural evolution, and properties. Chinese Chemical Letters, 2026, 37(2): 111629-. doi: 10.1016/j.cclet.2025.111629
12. [12]
  Xingyu Chen , Sihui Zhuang , Weiyao Yan , Zhengli Zeng , Jianguo Feng , Hongen Cao , Lei Yu . Synthesis, antibacterial evaluation, and safety assessment of Se@PLA as a potent bactericide against Xanthomonas oryzae pv. oryzae. Chinese Chemical Letters, 2024, 35(10): 109635-. doi: 10.1016/j.cclet.2024.109635
13. [13]
  Yaxuan Fu , Xiaozhi Jiang , Chenyang Shi , Long Chen , Zhendong Yang , Mengran Wang , Bo Hong , Faping Zhong , Yanqing Lai . The role of flame-retardant electrolytes in lithium-ion batteries: Custom design for improved battery-level safety. Chinese Chemical Letters, 2026, 37(4): 110972-. doi: 10.1016/j.cclet.2025.110972
14. [14]
  Hong Wang , Zhenwen Zhao , Xiao Xu , Zhide Guo , Gang Liu . Ultra-low-dose radioimmunotherapy improves prostate cancer treatment efficacy and safety. Chinese Chemical Letters, 2026, 37(8): 111799-. doi: 10.1016/j.cclet.2025.111799
15. [15]
  Gaofeng WANG , Shuwen SUN , Yanfei ZHAO , Lixin MENG , Bohui WEI . Structural diversity and luminescence properties of three zinc coordination polymers based on bis(4-(1H-imidazol-1-yl)phenyl)methanone. Chinese Journal of Inorganic Chemistry, 2024, 40(5): 849-856. doi: 10.11862/CJIC.20230479
16. [16]
  Jinlian SHI , Xiaoru LIU , Zhongxuan XU . Ligand-directed construction of cobalt-oxo cluster-based organic frameworks: Structural modulation, semiconductor, and antiferromagnetic properties. Chinese Journal of Inorganic Chemistry, 2026, 42(1): 45-54. doi: 10.11862/CJIC.20250196
17. [17]
  Qing Zhang , Ling Sun , Lingyu Wu , Xue Wang , Liru Chen , Youyou Chen , Yuhang Liu , Wenhui Gu , Donglei Shi , Wenwen Liu , Jian Li , Yi-You Huang , Baoli Li , Hai-Bin Luo . Platycladus orientalis (L.) Franco demonstrates effective anti-psoriasis effects by inhibiting PDE4 with favorable safety profiles. Chinese Chemical Letters, 2025, 36(10): 110795-. doi: 10.1016/j.cclet.2024.110795
18. [18]
  Hongyu Tang , Dongming Liu , Jinfu Huang , Liang Zhang , Yang Tang , Bin Huang , Yanwei Li , Shunhua Xiao , Yiling Sun , Renheng Wang . Excellent structural stability and electrochemical properties of LiNi_0.9Co_0.05Mn_0.05O₂ material by surface Ni²⁺ anchoring and Cs⁺ doping. Chinese Chemical Letters, 2025, 36(6): 109987-. doi: 10.1016/j.cclet.2024.109987
19. [19]
  Jiaqi Liu , Sishi Li , Yandong Xie , Ziqiang Fan , Zhenyuan Miao , Pengwei Jing , Yuecong Chen , Jian Zhu , Chao Yang , Xingbin Yan . Surface engineering driven performance optimization of hard carbon for sodium ion storage. Chinese Chemical Letters, 2026, 37(7): 111112-. doi: 10.1016/j.cclet.2025.111112
20. [20]
  Shiwen Song , Mingyang Zhao , Xiangrong Song , Huaidong Yu , Xin Xu , Dong Sun , Jingkai Gu . Unraveling metabolic complexity of multi-payload PEG-irinotecan prodrug: A deconvolution-based LC-Q-TOF MS approach for preclinical pharmacokinetic characterization. Chinese Chemical Letters, 2026, 37(2): 112099-. doi: 10.1016/j.cclet.2025.112099

Get Citation

PDF

XML

Metrics

PDF Downloads(0)
Abstract views(20)
HTML views(0)

通讯作者: 陈斌, bchen63@163.com

1.
沈阳化工大学材料科学与工程学院沈阳 110142