Optimization of the in vitro cardiac safety of hydroxamate-based histone deacetylase inhibitors.

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.

• Authors: Michael D Shultz, Xueying Cao, Christine H Chen, Young Shin Cho, Nicole R Davis, Joe Eckman, Jianmei Fan, Alex Fekete, Brant Firestone, Julie Flynn, Jack Green, Joseph D Growney, Mats Holmqvist, Meier Hsu, Daniel Jansson, Lei Jiang, Paul Kwon, Gang Liu, Franco Lombardo, Qiang Lu, Dyuti Majumdar, Christopher Meta, Lawrence Perez, Minying Pu, Tim Ramsey, Stacy Remiszewski, Suzanne Skolnik, Martin Traebert, Laszlo Urban, Vinita Uttamsingh, Ping Wang, Steven Whitebread, Lewis Whitehead, Yan Yan-Neale, Yung-Mae Yao, Liping Zhou, Peter Atadja
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 54 Issue 13 Pg. 4752-72 (Jul 14 2011) ISSN: 1520-4804 [Electronic] United States
• PMID: 21650221 (Publication Type: Journal Article)

Chemical References

• Acrylamides
• Antineoplastic Agents
• ERG1 Potassium Channel
• Ether-A-Go-Go Potassium Channels
• Histone Deacetylase Inhibitors
• Hydroxamic Acids
• KCNH2 protein, human
• N-hydroxy-3-(4-(((2-(2-(1-hydroxy-1-methylethyl)-1H-indol-3-yl)ethyl)isopropylamino)methyl)phenyl)acrylamide
• N-hydroxy-3-(4-((2-(2-methylpyrazolo(1,5-a)pyridin-3-yl)ethylamino)methyl)phenyl)acrylamide

Topics

• Acrylamides (chemical synthesis, pharmacology, toxicity)
• Animals
• Antineoplastic Agents (chemical synthesis, pharmacology, toxicity)
• Drug Screening Assays, Antitumor
• ERG1 Potassium Channel
• Ether-A-Go-Go Potassium Channels (antagonists & inhibitors)
• HCT116 Cells
• Half-Life
• Histone Deacetylase Inhibitors (chemical synthesis, pharmacology, toxicity)
• Humans
• Hydroxamic Acids (chemical synthesis, pharmacology, toxicity)
• In Vitro Techniques
• Mice
• Mice, Nude
• Microsomes, Liver (metabolism)
• Models, Molecular
• Neoplasm Transplantation
• Patch-Clamp Techniques
• Radioligand Assay
• Rats
• Rats, Sprague-Dawley
• Stereoisomerism
• Structure-Activity Relationship
• Tissue Distribution
• Transplantation, Heterologous