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Optimization of the in Vitro Cardiac Safety of Hydroxamate-Based Histone Deacetylase Inhibitors
- Source :
- Journal of Medicinal Chemistry. 54:4752-4772
- Publication Year :
- 2011
- Publisher :
- American Chemical Society (ACS), 2011.
-
Abstract
- Histone deacetylase (HDAC) inhibitors have shown promise in treating various forms of cancer. However, many HDAC inhibitors from diverse structural classes have been associated with QT prolongation in humans. Inhibition of the human ether a-go-go related gene (hERG) channel has been associated with QT prolongation and fatal arrhythmias. To determine if the observed cardiac effects of HDAC inhibitors in humans is due to hERG blockade, a highly potent HDAC inhibitor devoid of hERG activity was required. Starting with dacinostat (LAQ824), a highly potent HDAC inhibitor, we explored the SAR to determine the pharmacophores required for HDAC and hERG inhibition. We disclose here the results of these efforts where a high degree of pharmacophore homology between these two targets was discovered. This similarity prevented traditional strategies for mitigating hERG binding/modulation from being successful and novel approaches for reducing hERG inhibition were required. Using a hERG homology model, two compounds, 11r and 25i, were discovered to be highly efficacious with weak affinity for the hERG and other ion channels.
- Subjects :
- Models, Molecular
ERG1 Potassium Channel
congenital, hereditary, and neonatal diseases and abnormalities
Patch-Clamp Techniques
Transplantation, Heterologous
hERG
Mice, Nude
Antineoplastic Agents
In Vitro Techniques
Pharmacology
Hydroxamic Acids
Rats, Sprague-Dawley
Mice
Radioligand Assay
Structure-Activity Relationship
Drug Discovery
Animals
Humans
Structure–activity relationship
Tissue Distribution
cardiovascular diseases
Homology modeling
Ion channel
Acrylamides
biology
Chemistry
Stereoisomerism
HCT116 Cells
Ether-A-Go-Go Potassium Channels
In vitro
Rats
Histone Deacetylase Inhibitors
Transplantation
Microsomes, Liver
biology.protein
Molecular Medicine
Histone deacetylase
Drug Screening Assays, Antitumor
Pharmacophore
Neoplasm Transplantation
Half-Life
Subjects
Details
- ISSN :
- 15204804 and 00222623
- Volume :
- 54
- Database :
- OpenAIRE
- Journal :
- Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....c444090ceb6d32a590072a95df83c006