Improved Synthesis and Structural Reassignment of MC1568: A Class IIa Selective HDAC Inhibitor

Fleming, Cassandra L.; Ashton, Trent D.; Gaur, Vidhi; McGee, Sean L.; Pfeffer, Frederick M.

doi:10.1021/jm401945k

Cited by 39 publications

(26 citation statements)

References 21 publications

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“…MC1568 has been demonstrated to have selective inhibition of class IIa HDACs, without affecting other HDAC classes, at least in part by inducing degradation of HDAC4 and HDAC5. 22, 23 We found that treatment of PAECs with MC1568 led to a significant decrease in the protein levels of HDAC4 and HDAC5 (Sup. Fig.…”

Section: Resultsmentioning

confidence: 87%

Restoration of Impaired Endothelial Myocyte Enhancer Factor 2 Function Rescues Pulmonary Arterial Hypertension

et al. 2015

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Background Pulmonary arterial hypertension (PAH) is a progressive disease of the pulmonary arterioles, characterized by increased pulmonary arterial pressure and right ventricular failure. The etiology of PAH is complex, but aberrant proliferation of the pulmonary artery endothelial cells (PAECs) and pulmonary artery smooth muscle cells (PASMCs) is thought to play an important role in its pathogenesis. Understanding the mechanisms of transcriptional gene regulation involved in pulmonary vascular homeostasis can provide key insights into potential therapeutic strategies. Methods and Results We demonstrate that the activity of the transcription factor myocyte enhancer factor 2 (MEF2) is significantly impaired in the PAECs derived from subjects with PAH. We identified MEF2 as the key cis-acting factor that regulates expression of a number of transcriptional targets involved in pulmonary vascular homeostasis, including microRNAs 424 and 503, connexins 37, connexin 40, Krűppel Like Factor 2 (KLF2) and KLF4, which were found to be significantly decreased in PAH PAECs. The impaired MEF2 activity in PAH PAECs was mediated by excess nuclear accumulation of two class IIa histone deacetylases (HDACs) that inhibit its function, namely HDAC4 and HDAC5. Selective, pharmacologic inhibition of class IIa HDACs led to restoration of MEF2 activity in PAECs, as demonstrated by increased expression of its transcriptional targets, decreased cell migration and proliferation, and rescue of experimental pulmonary hypertension (PH) models. Conclusions Our results demonstrate that strategies to augment MEF2 activity holds potential therapeutic value in PAH. Moreover, we identify selective HDAC IIa inhibition as a viable alternative approach to avoid the potential adverse effects of broad spectrum HDAC inhibition in PAH.

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Section: Resultsmentioning

confidence: 87%

Restoration of Impaired Endothelial Myocyte Enhancer Factor 2 Function Rescues Pulmonary Arterial Hypertension

et al. 2015

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“…MC1568 and MC1575 are derivatives of aroyl-pyrrolyl–hydroxyamides (APHAs), showing selectivity towards Class IIa HDACs and HDAC6 (Mai et al 2005; Fleming et al 2014). Although Class IIa HDACs are mainly involved in tissue-specific growth and differentiation, rather than in cell proliferation, MC1568 and MC1575 treatment still displayed anti-proliferative effects in estrogen receptor (ER)–positive breast cancer cells (Duong et al 2008) as well as human melanoma cells (Venza et al 2013).…”

Section: Anticancer Effect Of Hdac Inhibitorsmentioning

confidence: 99%

HDACs and HDAC Inhibitors in Cancer Development and Therapy

Seto

2016

Cold Spring Harb Perspect Med

960

765

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Over the last several decades, it has become clear that epigenetic abnormalities may be one of the hallmarks of cancer. Post-translational modifications of histones, for example, may play a crucial role in cancer development and progression by modulating gene transcription, chromatin remodeling and nuclear architecture. Histone acetylation, a well-studied post-translational histone modification, is controlled by the opposing activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs). By removing acetyl groups, HDACs reverse chromatin acetylation and alter transcription of oncogenes and tumor suppressor genes. In addition, HDACs deacetylate numerous non-histone cellular substrates that govern a wide array of biological processes including cancer initiation and progression. This review will discuss the role of HDACs in cancer and the therapeutic potential of HDAC inhibitors (HDACi) as emerging drugs in cancer treatment.

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“…First, analysis of NMR spectra revealed that commercially available MC1568 is an isomer of the published structure. Of note, a recent medicinal chemistry report of the re‐synthesis of MC1568 defined the major synthetic product to be the same isomer sold by Sigma and Selleck [36]. As such, we cannot rule out the possibility that the differential effects on class IIa HDAC activity are due to distinct properties of the isomers.…”

Section: Discussionmentioning

confidence: 96%

Promiscuous actions of small molecule inhibitors of the protein kinase D‐class IIa HDAC axis in striated muscle

Lemon¹,

Harrison²,

Horn³

et al. 2015

FEBS Letters

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PKD-mediated phosphorylation of class IIa HDACs frees the MEF2 transcription factor to activate genes that govern muscle differentiation and growth. Studies of the regulation and function of this signaling axis have involved MC1568 and Gö-6976, which are small molecule inhibitors of class IIa HDAC and PKD catalytic activity, respectively. We describe unanticipated effects of these compounds. MC1568 failed to inhibit class IIa HDAC catalytic activity in vitro, and exerted divergent effects on skeletal muscle differentiation compared to a bona fide inhibitor of these HDACs. In cardiomyocytes, Gö-6976 triggered calcium signaling and activated stress-inducible kinases. Based on these findings, caution is warranted when employing MC1568 and Gö-6976 as pharmacological tool compounds to assess functions of class IIa HDACs and PKD.

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Improved Synthesis and Structural Reassignment of MC1568: A Class IIa Selective HDAC Inhibitor

Abstract: An improved synthesis and structural reassignment of the class IIa selective histone deacetylase (HDAC) inhibitor MC1568 are described.

Cited by 39 publications

References 21 publications

Restoration of Impaired Endothelial Myocyte Enhancer Factor 2 Function Rescues Pulmonary Arterial Hypertension

Restoration of Impaired Endothelial Myocyte Enhancer Factor 2 Function Rescues Pulmonary Arterial Hypertension

HDACs and HDAC Inhibitors in Cancer Development and Therapy

Promiscuous actions of small molecule inhibitors of the protein kinase D‐class IIa HDAC axis in striated muscle

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