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Updated: Mar 20, 2026
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Assays for Validating Histone Acetyltransferase Inhibitors
Published on: August 6, 2020
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Histone Deacetylase Inhibitors Prolong Cardiac Repolarization through Transcriptional Mechanisms
Stan Spence1, Mark Deurinck2, Haisong Ju3
1*Preclinical Safety, Novartis Institutes of Biomedical Research, 100 Technology Square, Cambridge, MA 02139 stanley.spence@novartis.com.
Summary
Histone deacetylase (HDAC) inhibitors, used in cancer therapy, can delay cardiac repolarization. This study suggests HDAC inhibitors may affect heart rhythm by altering genes involved in ion channel function, not direct channel blockade.
Area of Science:
- Pharmacology
- Cardiology
- Molecular Biology
Background:
- Histone deacetylase (HDAC) inhibitors are anticancer drugs that affect gene expression.
- Clinical use of HDAC inhibitors is linked to cardiac repolarization delays and torsades de pointes.
- The mechanism behind HDAC inhibitor cardiotoxicity remains unclear.
Purpose of the Study:
- To investigate the mechanism of HDAC inhibitor-induced cardiac repolarization abnormalities.
- To determine if HDAC inhibitors directly affect cardiac ion channels or alter gene expression related to them.
Main Methods:
- Administration of diverse HDAC inhibitors to dogs to measure cardiac repolarization (QTc interval).
- Transcriptional profiling of ventricular myocardium to identify affected genes.
- In vitro ion channel assays (binding and patch clamp) and cellular studies using hERG channel mutants and wild-type variants.
Main Results:
- HDAC inhibitors caused delayed but persistent QTc interval prolongation in dogs.
- Transcriptional profiling revealed alterations in genes related to ion channel trafficking and localization.
- In vitro studies showed HDAC inhibitors rescued trafficking-deficient hERG mutants and affected wild-type hERG maturation, correlating with QTc prolongation.
- Direct ion channel blockade by HDAC inhibitors showed no consistent correlation with QTc prolongation.
Conclusions:
- HDAC inhibitor-induced cardiac repolarization prolongation may be mediated by transcriptional changes affecting ion channel trafficking and sarcolemmal localization.
- These findings suggest delayed assessment of physiological effects relative to Tmax/Cmax for epigenetic drugs.
- The study provides insights into the cardiotoxicity mechanisms of HDAC inhibitors, crucial for drug development.
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