Synthesis and Biological Evaluation of 3-(4-Substituted-phenyl)-<i>N</i>-hydroxy-2-propenamides, a New Class of Histone Deacetylase Inhibitors

Kim, Dae Kee; Lee, Ju Young; Kim, Jae Sun; Ryu, Je Ho; Choi, Jin Young; Lee, Junwon; Im, Guang Jin; Kim, Tae Kon; Seo, Jung Woo T.; Park, Hyun Ju; Yoo, Jakyung; Park, Jung Hyun; Bang, Yung Jue

doi:10.1021/jm030377q

Cited by 44 publications

(20 citation statements)

References 32 publications

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“…For example, MS-275 preferentially inhibits HDAC1 with IC 50 , at 0.3 mM, compared to HDAC3 with an IC 50 of about 8 mM, and has little or no inhibitory effect against HDAC6 and HDAC8 (Hu et al, 2003). Two novel synthetic compounds, SK7041 and SK7068, preferentially target HDAC1 and 2 and exhibit growth inhibitory effects in human cancer cell lines and tumor xenograft models (Kim et al, 2003a). A small molecule, tubacin, selectively inhibits HDAC6 activity and causes an accumulation of acetylated atubulin, but does not affect acetylation of histones, and does not inhibit cell cycle progression (Haggarty et al, 2003).…”

Section: Hdacimentioning

confidence: 99%

Histone deacetylase inhibitors: molecular mechanisms of action

2007

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Section: Hdacimentioning

confidence: 99%

Histone deacetylase inhibitors: molecular mechanisms of action

2007

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“…One of these new HDAC inhibitors, 3-(4-substituted phenyl)-Nhydroxy-2-propenamide (SK-7041 [SK]), 13 was found to have high selectivity to HDAC1 and HDAC2, both belonging to the class I HDAC family. 9 To test whether cardiac hypertrophy induced by pressure overload could be prevented by class I-selective HDAC inhibition, we treated AB mice with SK.…”

Section: Prevention Of Cardiac Hypertrophy By Sk-7041 a Class I Hdacmentioning

confidence: 99%

Inhibition of Histone Deacetylation Blocks Cardiac Hypertrophy Induced by Angiotensin II Infusion and Aortic Banding

et al. 2006

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Background-A number of distinct stress signaling pathways in myocardium cause cardiac hypertrophy and heart failure.Class II histone deacetylases (HDACs) antagonize several stress-induced pathways and hypertrophy. However, cardiac hypertrophy induced by transgenic overexpression of the homeodomain only protein, HOP, can be prevented by the nonspecific HDAC inhibitors trichostatin A and valproic acid, suggesting that alternate targets that oppose class II HDAC function might exist in myocardium. We tested the effects of several HDAC inhibitors, including a class I HDAC-selective inhibitor, SK-7041, on cardiac hypertrophy induced by angiotensin II (Ang II) treatment or aortic banding (AB). Methods and Results-Cardiac hypertrophy was induced by chronic infusion of Ang II or by AB in mice or rats and evaluated by determining the ratio of heart weight to body weight or to tibia length, cross-sectional area, or echocardiogram. Cardiac hypertrophy induced by Ang II or AB for 2 weeks was significantly reduced by simultaneous administration of trichostatin A, valproic acid, or SK-7041. Echocardiogram revealed that exaggerated left ventricular systolic dimensions were relieved by HDAC inhibitors. HDAC inhibitors partially reversed preestablished cardiac hypertrophy and improved survival of AB mice. The expressions of atrial natriuretic factor, ␣-tubulin, ␤-myosin heavy chain, and interstitial fibrosis were reduced by HDAC inhibition. Conclusions-These results suggest that the predominant effect of HDAC inhibition, mainly mediated by class I HDACs, is to prevent cardiac hypertrophy in response to a broad range of agonist and stretch stimuli.

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“…SK-7068 effectively inhibited HDACs at nanomolar concentrations in vitro and showed significant anti-tumor effects in tumor-bearing mice. 67,68 Target enzyme specificity. Not all HDACs are equally sensitive to HDACIs.…”

Section: Histone Deacetylase Inhibitors (Hdacis)mentioning

confidence: 99%

Histone Deacetylase Inhibitors for Cancer Therapy

Kim¹,

Bang²,

Robertson³

2006

Epigenetics

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The epigenome of cancer cells is determined by DNA methylation and an array of post-translational modifications of the core histones. Epigenetic abnormalities are commonly found in human tumors and importantly, they can be reversed by pharmacologic inhibitors. Histone deacetylase inhibitors (HDACIs) represent one of the most promising epigenetic treatments for cancer. HDACIs have emerged as promising targets for cancer therapy because they reactivate the transcription of multiple genes that are silenced in human tumors and they show pleiotropic anti-tumor effects selectively in cancer cells. HDACIs are well-tolerated and several show promising anti-tumor activity. While gene transcription has been considered to be the major target of HDACIs, inhibition of acetylation of non-histone proteins is now emerging as a novel basis for their anti-tumor effects. In this review, we discuss new insights into the molecular mechanism of HDACIs, their current status of clinical development, and possible future uses in cancer therapy.

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Synthesis and Biological Evaluation of 3-(4-Substituted-phenyl)-N-hydroxy-2-propenamides, a New Class of Histone Deacetylase Inhibitors

Cited by 44 publications

References 32 publications

Histone deacetylase inhibitors: molecular mechanisms of action

Histone deacetylase inhibitors: molecular mechanisms of action

Inhibition of Histone Deacetylation Blocks Cardiac Hypertrophy Induced by Angiotensin II Infusion and Aortic Banding

Histone Deacetylase Inhibitors for Cancer Therapy

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