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Optimization of the in vitro Cardiac Safety of Hydroxamate-Based Histone Deacetylase Inhibitors

Shultz, Michael and Cao, Xueying and Chen, Christine and Cho, Young and Davis, Nicole and Eckman Iii, Joseph and Growney, Joseph and Holmqvist, Mats and Hsu, Meier and Jansson, Daniel and Jiang, Lei and Kwon, Paul and Liu, Gang and Lombardo, Franco and Lu, Qiang and Majumdar, Dyuti and Meta, Christopher and Pu, Minying and Ramsey, Timothy and Remiszewski, Stacy and Traebert, Martin and Urban, Laszlo and Uttamsingh, Vinita and Wang, Ping and Whitebread, Steven and Whitehead, Lewis and Yan-Neale, Yan and Yao, Megan and Zhou, Liping and Atadja, Peter (2011) Optimization of the in vitro Cardiac Safety of Hydroxamate-Based Histone Deacetylase Inhibitors. Journal of Medicinal Chemistry, 54 (13). pp. 4752-4772. ISSN 0022-2623

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. In order 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 in vivo with weak affinity for the hERG and other ion channels.

Item Type: Article
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Keywords: HDAC, hERG
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Date Deposited: 13 Oct 2015 13:15
Last Modified: 13 Oct 2015 13:15
URI: https://oak.novartis.com/id/eprint/4009

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