Class I Histone Deacetylase-Selective Novel Synthetic Inhibitors Potently Inhibit Human Tumor Proliferation

Park, Jung Hyun; Jung, Yeonjoo; Kim, Tai Young; Kim, Sang Gyun; Jong, Hyun Soon; Lee, Sang Eun; Kim, Dae Kee; Lee, Jong Soo; Kim, Noe Kyeong; Kim, Tae You; Bang, Yung Jue

doi:10.1158/1078-0432.ccr-03-0709

Cited by 142 publications

(88 citation statements)

References 30 publications

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“…Assessing HDAC inhibitor selectivity in vitro must be approached with caution since active enzymes consist of a multiprotein complex containing other HDACs and cofactors. In agreement with our data, Park et al (2004) and Kraker et al (2003) also observed modest activity of MS-275 while using immunoprecipitated HDAC1 multiprotein complexes from cancer cells. It therefore appears likely that MS-275 inhibits HDAC1 in its endogenously biologically active multiprotein complex less potently than as a recombinant protein.…”

Section: Discussionsupporting

confidence: 93%

R306465 is a novel potent inhibitor of class I histone deacetylases with broad-spectrum antitumoral activity against solid and haematological malignancies

Arts¹,

Angibaud²,

Marien³

et al. 2007

Br J Cancer

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R306465 is a novel hydroxamate-based histone deacetylase (HDAC) inhibitor with broad-spectrum antitumour activity against solid and haematological malignancies in preclinical models. R306465 was found to be a potent inhibitor of HDAC1 and -8 (class I) in vitro. It rapidly induced histone 3 (H3) acetylation and strongly upregulated expression of p21 waf1,cip1 , a downstream component of HDAC1 signalling, in A2780 ovarian carcinoma cells. R306465 showed class I HDAC isotype selectivity as evidenced by poor inhibition of HDAC6 (class IIb) confirmed by the absence of downregulation of Hsp90 chaperone c-raf protein expression and tubulin acetylation. This distinguished it from other HDAC inhibitors currently in clinical development that were either more potent towards HDAC6 (e.g. vorinostat) or had a broader HDAC inhibition spectrum (e.g. panobinostat). R306465 potently inhibited cell proliferation of all main solid tumour indications, including ovarian, lung, colon, breast and prostate cancer cell lines, with IC 50 values ranging from 30 to 300 nM. Haematological cell lines, including acute lymphoblastic leukaemia, acute myeloid leukaemia, chronic lymphoblastic leukaemia, chronic myeloid leukaemia, lymphoma and myeloma, were potently inhibited at a similar concentration range. R306465 induced apoptosis and inhibited angiogenesis in cell-based assays and had potent oral in vivo antitumoral activity in xenograft models. Once-daily oral administration of R306465 at well-tolerated doses inhibited the growth of A2780 ovarian, H460 lung and HCT116 colon carcinomas in immunodeficient mice. The high activity of R306465 in cell-based assays and in vivo after oral administration makes R306465 a promising novel antitumoral agent with potential applicability in a broad spectrum of human malignancies.

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Section: Discussionsupporting

confidence: 93%

R306465 is a novel potent inhibitor of class I histone deacetylases with broad-spectrum antitumoral activity against solid and haematological malignancies

Arts¹,

Angibaud²,

Marien³

et al. 2007

Br J Cancer

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“…The newly formed chromatin structure (directly, or through recruitment of accessory factors) determines an altered pattern of transcription (for coding areas), or of DNA replication or repair, which cooperate in the transformed phenotype. class 2 HDACs, and even fewer (that is, tubacin for HDAC6) are able to discriminate efficiently among HDACs that belong to the same class [72][73][74][75] . At present, this limitation has little relevance to the use of HDACi as potential anti-tumour drugs as there is no definitive evidence that distinct HDACs have a defined role in cancer.…”

Section: Inhibiting Hdacsmentioning

confidence: 99%

Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer

2006

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| Histone deacetylases (HDACs) are considered to be among the most promising targets in drug development for cancer therapy, and first-generation histone deacetylase inhibitors (HDACi) are currently being tested in phase I/II clinical trials. A wide-ranging knowledge of the role of HDACs in tumorigenesis, and of the action of HDACi, has been achieved. However, several basic aspects are not yet fully understood. Investigating these aspects in the context of what we now understand about HDACi action both in vitro and in vivo will further improve the design of optimized clinical protocols.Histone deacetylases (HDACs) have been intensively scrutinized over the past few years for two main reasons. First, they have been linked mechanistically to the pathogenesis of cancer, as well as several other diseases. Second, small-molecule HDAC inhibitors (HDACi) exist that have the capacity to interfere with HDAC activity and can therefore achieve significant biological effects in preclinical models of cancer. These findings justified the introduction of HDACi into clinical trials. These initial clinical trials have just ended and show encouraging results. At this stage it is crucial to evaluate whether our current knowledge on the mechanisms of tumorigenesis that are linked to HDACs, and on the mechanisms of tumour sensitivity to HDACi, is firm enough to improve the design of further clinical trials. Recent structural and chemical data have emerged that will help in the design of novel HDACi with more desirable properties than the existing ones. However, key areas of investigation that might help to further illuminate the design of successful HDACi-based cancer therapy remain poorly explored. Novel findings indicate that our understanding of how HDACi work will probably change significantly, establishing a new paradigm in the field of intelligent drug design with broad implications for the design of targeted therapies in cancer and possibly other diseases.HDACs: enzymes looking for substrate(s) Four HDAC classes have been identified (FIG. 1a). One of them (class 3 or the so-called sirtuins, from the yeast protein Sir2) constitutes a structurally unrelated, NADdependent subfamily, and will not be considered here; neither will the class 3-specific HDACi, which are less characterized than those for the other classes 1 .An extensive phylogenetic analysis of HDACs has been performed 2,3 . HDACs are members of an ancient enzyme family found in animals, plants, fungi and bacteria. It is thought that HDACs evolved in the absence of histone proteins. Indeed, eukaryotic HDACs can deacetylate non-histone as well as histone substrates, and some HDACs reside in the cytoplasm (where histones are synthesized and acetylated for proper assembly, without the intervention of HDACs) and in mitochondria (where histones are absent).Are HDACs, then, truly HDACs 4 ? We postulate that key HDAC substrates might not be histones, but instead belong to the growing list of acetylated non-histone proteins (FIG. 1b and Supplementary information S1 ...

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“…For example, TSA was found to be a potent inhibitor of HDACs 1, 3, and 8 while MS-275 (2-Aminophenyl) 4-[(N-pyrydin-3-Metyloxycarbonyl)-(Aminomethyl)-(benzamide)] preferentially inhibited HDAC1 with IC50 at 0.3mM compared to HDAC3 with a IC50 of about 8 mM and no inhibitory effect against HDAC8 [Hu et al, 2003]. Two novel synthetic compounds, have been identified as HDAC inhibitors: SK 7041 and SK-7046 which preferentially target HDAC1 and 2 and exhibit growth inhibitory effects in human cancer cell lines and in tumor xenograft models [Park et al, 2004].…”

Section: Histone Deacetylase Inhibitorsmentioning

confidence: 99%

Prospects: Histone deacetylase inhibitors

Dokmanovic

Marks

2005

J of Cellular Biochemistry

441

363

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Histone deacetylase (HDAC), inhibitors represent a new class of targeted anti-cancer agents. Several of these compounds are in clinical trials with significant activity against a spectrum of both hematologic and solid tumors at doses that are well tolerated by the patients. The HDAC inhibitors are a structurally diverse group of molecules that can induce growth arrest, differentiation, apoptosis, and autophagocytic cell death of cancer cells. While the base sequence of DNA provides the genetic code for proteins, the expression of genes is regulated, in large part, by the structure of the chromatin proteins around which the DNA is wrapped (epigenetic gene regulation). The acetylation and deacetylation of the lysines in the tails of the core histones, among the most extensively studied aspects of chromatin structure, is controlled by the action of two families of enzymes, histone deacetylases (HDACs) and histone acetyltransferases (HATs). Protein components of transcription factor complexes and many other non-histone proteins are also substrates for HDACs and HATs. The structure and activity of these non-histone proteins may be altered by acetylation/deacetylation with consequent effects on various cell functions including gene expression, cell cycle progression, and cell death pathways. This review focuses on several key questions with respect to the mechanism of action of HDACi, including, what are the different cell phenotypes induced by HDACi, why are normal cells compared to transformed cells relatively resistant to HDACi induced cell death, why are certain tumors more responsive to HDACi than others, and what is the basis of the selectivity of HDACi in altering gene expression. The answers to these questions will have therapeutic importance since we will identify targets for enhancing the efficacy and safety of HDACi.

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Class I Histone Deacetylase-Selective Novel Synthetic Inhibitors Potently Inhibit Human Tumor Proliferation

Cited by 142 publications

References 30 publications

R306465 is a novel potent inhibitor of class I histone deacetylases with broad-spectrum antitumoral activity against solid and haematological malignancies

R306465 is a novel potent inhibitor of class I histone deacetylases with broad-spectrum antitumoral activity against solid and haematological malignancies

Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer

Prospects: Histone deacetylase inhibitors

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