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Method for Identifying Small Molecule Inhibitors of the Protein-protein Interaction Between HCN1 and TRIP8b
Published on: November 11, 2016
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Crizotinib Inhibits Hyperpolarization-activated Cyclic Nucleotide-Gated Channel 4 Activity
Zhushan Zhang1, Tai-Qin Huang1, Igor Nepliouev1
1Department of Medicine, Duke University Medical Center, Durham, NC USA 27710.
Cardio-Oncology (London, England)
|February 21, 2017
Summary
Crizotinib, used for lung cancer, can slow heart rate by directly affecting cardiac pacemaker cells. This drug inhibits the HCN4 channel, which is crucial for regulating heart rhythm.
Area of Science:
- Cardiology
- Pharmacology
- Oncology
Background:
- Sinus bradycardia is a common side effect in patients treated with crizotinib, an anaplastic lymphoma kinase (ALK) inhibitor for non-small cell lung cancer (NSCLC).
- Investigated potential direct cardiac effects of crizotinib on heart rate (HR).
Purpose of the Study:
- To determine if crizotinib directly influences heart rate through cardiac mechanisms.
- To elucidate the specific ion channel targets responsible for crizotinib-induced bradycardia.
Main Methods:
- Utilized Langendorff-perfused mouse hearts with ECG analysis to assess crizotinib's effect on HR.
- Employed whole-cell patch clamp technique on mouse sinoatrial node cells (SANCs) and HEK-293 cells expressing human HCN4 to study If currents.
Main Results:
- Crizotinib caused a dose-dependent reduction in HR in isolated mouse hearts (IC50 = 1.7 ± 0.4 μmol/L) without altering cardiac conduction intervals (PR, QRS, QT).
- Crizotinib inhibited the hyperpolarization-activated funny current (If) in SANCs, a key regulator of cardiac pacemaking.
- Diminished HCN4 channel activity (IC50 = 1.4 ± 0.3 μmol/L), slowed activation, and shifted the activation curve of HCN4.
Conclusions:
- Crizotinib's inhibition of HCN4 channels is a primary mechanism underlying its bradycardic effects.
- These findings highlight the direct impact of crizotinib on cardiac electrophysiology.
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