Optimization of the in Vitro Cardiac Safety of Hydroxamate-Based Histone Deacetylase Inhibitors
- 8 June 2011
- journal article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 54 (13), 4752-4772
- https://doi.org/10.1021/jm200388e
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.Keywords
This publication has 66 references indexed in Scilit:
- Phase 2 trial of romidepsin in patients with peripheral T-cell lymphomaBlood, 2011
- Romidepsin (Istodax, NSC 630176, FR901228, FK228, depsipeptide): a natural product recently approved for cutaneous T-cell lymphomaThe Journal of Antibiotics, 2011
- Acetylation Directs Survivin Nuclear Localization to Repress STAT3 Oncogenic ActivityJournal of Biological Chemistry, 2010
- The Protein Stability of Axin, a Negative Regulator of Wnt Signaling, Is Regulated by Smad Ubiquitination Regulatory Factor 2 (Smurf2)Published by Elsevier BV ,2010
- Myristoylation and Membrane Binding Regulate c-Src Stability and Kinase ActivityMolecular and Cellular Biology, 2010
- Histone Deacetylase: A Potential Therapeutic Target for Fibrotic DisordersJournal of Pharmacology and Experimental Therapeutics, 2010
- The Emerging Characterization of Lysine Residue Deacetylation on the Modulation of Mitochondrial Function and Cardiovascular BiologyCirculation Research, 2009
- Acetylated NPM1 Localizes in the Nucleoplasm and Regulates Transcriptional Activation of Genes Implicated in Oral Cancer ManifestationMolecular and Cellular Biology, 2009
- The HDAC inhibitor 4b ameliorates the disease phenotype and transcriptional abnormalities in Huntington's disease transgenic miceProceedings of the National Academy of Sciences of the United States of America, 2008
- c‐Abl acetylation by histone acetyltransferases regulates its nuclear–cytoplasmic localizationEMBO Reports, 2006