A Potent Fluorescent Reversible-Covalent Inhibitor of Cardiac Muscle Contraction

Fangze Cai, Thomas Kampourakis, Brittney A. Klein, Brian D. Sykes*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)


Compounds that directly modulate the response of the cardiac sarcomere have potential in the treatment of cardiac disease. While a number of sarcomere activators have been discovered and extensively studied, very few inhibitors have been identified. We report a potent cardiac sarcomere inhibitor, DN-F01, targeting the cardiac muscle thin filament protein troponin complex. Functional studies show that DN-F01 has a strong inhibitory calcium-dependent effect on cardiac myofibrillar ATPase activity with an IC50 value of 11 ± 4 nmol/L. DN-F01 is shown to bind to a cardiac troponin C-troponin I chimera (cChimera) with a KD of μ50 nM using fluorescence spectroscopy, indicating that troponin is the likely target for DN-F01. NMR titrations of DN-F01 to C35S and A-Cys cChimera show covalent and noncovalent binding of DN-F01 bound to the calcium-saturated cChimera.

Original languageEnglish
Pages (from-to)1503-1507
Number of pages5
JournalAcs Medicinal Chemistry Letters
Issue number9
Publication statusPublished - 9 Sept 2021


  • cardiac
  • inhibitor
  • sarcomere
  • troponin


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