Discovery of a Potent Class I Selective Ketone Histone Deacetylase Inhibitor with Antitumor Activity in Vivo and Optimized Pharmacokinetic Properties

Kinzel, Olaf; Llauger-Bufi, Laura; Pescatore, Giovanna; Rowley, Michael; Schultz‐Fademrecht, Carsten; Monteagudo, Edith; Fonsi, Massimiliano; Paz, Odalys Gonzalez; Fiore, F.; Steinkühler, Christian; Jones, Philip

doi:10.1021/jm9004303

Cited by 42 publications

(37 citation statements)

References 23 publications

(44 reference statements)

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“…29,30 BRD7914 and similar derivatives have shown some efficacy in vitro and in vivo and appear to have a better metabolic profile than SAHA. 30,31 BRD7914 was associated that target DNA damage response and repair pathways to induce synthetic lethality as a treatment strategy. 3 That chromatin modulating HDACi cause DNA damage via direct and indirect mechanisms preferentially in tumor cells, suggest these compounds could be used similarly to treat ovarian cancers.…”

Section: Robust Induction Of Ph2ax Is Tightly Associated With the Cytmentioning

confidence: 99%

The DNA damage mark pH2AX differentiates the cytotoxic effects of small molecule HDAC inhibitors in ovarian cancer cells

Wilson

Holson

Wagner

et al. 2011

Cancer Biology & Therapy

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High grade epithelial ovarian cancers are relatively sensitive to DNA damaging platinum-based chemotherapy, suggesting that the dependencies of ovarian tumors on DNA damage response pathways can be harnessed for therapeutic purposes. Our goal was to determine if the DNA damage mark gamma-H2AX phosphorylation (pH2AX) could be used to identify suitable cytotoxic histone deacetylase inhibitors (HDACi) for ovarian cancer treatment. Nineteen chemically diverse HDACi compounds were tested in 7 ovarian cancer cell lines. Fluorescent, biochemical and cell-based assays were performed to assess DNA damage by induction of pH2AX and to measure cell viability and apoptosis. The relationships between pH2AX and the cellular effects of cell viability and apoptosis were calculated. Selected HDACi were tested in combination with cisplatin and other DNA damaging agents to determine if the HDACi improved upon the effects of the DNA damaging agents. The HDACi compounds induced differing levels of pH2AX expression. High levels of pH2AX in HDACi-treated ovarian cancer cells were tightly associated with decreased cell viability and increased apoptosis. Consequently, a ketone-based HDACi was chosen and found to enhance the effects of cisplatin, even in ovarian cancer cells with extreme resistance to DNA damaging drugs. In conclusion, a fluorescent-based assay for pH2AX can be used to determine cellular responses to HDACi in vitro and may be a useful tool to identify potentially more effective HDACi for the treatment of ovarian cancer. In addition, these results lend support to the inclusion of ketone-derived HDACi compounds for future development.

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Section: Robust Induction Of Ph2ax Is Tightly Associated With the Cytmentioning

confidence: 99%

The DNA damage mark pH2AX differentiates the cytotoxic effects of small molecule HDAC inhibitors in ovarian cancer cells

Wilson

Holson

Wagner

et al. 2011

Cancer Biology & Therapy

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“…Previous research in our laboratories led to a novel series of heterocyclic inhibitors of human class-I HDACs represented by compound 3 (Figure 1). 23 This compound class features a central heterocycle that displays the pharmacophore elements common to many inhibitors of HDAC enzymes. Thus, a zinc binding group (ZBG) believed to interact with the catalytic metal ion of the HDAC enzyme is anchored by an alkyl linker.…”

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confidence: 99%

Discovery of a Selective Series of Inhibitors of Plasmodium falciparum HDACs

Ontoria

Paonessa

Ponzi

et al. 2016

ACS Med. Chem. Lett.

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The identification of a new series of P. falciparum growth inhibitors is described. Starting from a series of known human class I HDAC inhibitors a SAR exploration based on growth inhibitory activity in parasite and human cells-based assays led to the identification of compounds with submicromolar inhibition of P. falciparum growth (EC 50 < 500 nM) and good selectivity over the activity of human HDAC in cells (up to >50-fold). Inhibition of parasital HDACs as the mechanism of action of this new class of selective growth inhibitors is supported by hyperacetylation studies.KEYWORDS: Malaria, Plasmodium falciparum, PfHDAC1, 4-arylimidazoles I nfection with malaria parasites such as Plasmodium falciparum remains a devastating cause of death in tropical geographies with 40% of the world population at risk of acquiring the disease. There are approximately 200 million clinical cases of malaria every year leading to an estimated 600,000 deaths.1 The requirement for improved therapies to treat and to cure malaria is an evident medical and humanitarian need that is exacerbated by an alarming rise in parasite resistance to the current standard of care.2,3 Drugs that operate via novel mechanisms of action for which no innately resistant parasites are expected are therefore especially desirable.DNA is tightly packed around histone proteins in the nucleus of eukaryotic cells with its transcription being regulated by chemical modifications to the nucleosomal histone proteins themselves. Histone deacetylases (HDACs) are zinc-dependent enzymes that play crucial roles in modulating mammalian cell chromatin structure, transcription, and gene expression. 4−6HDACs have also been identified as important regulators of transcription in P. falciparum, 7−10 and inhibition of P. falciparum histone deacetylases (Pf HDACs) has been reported to both effectively kill the parasites (Vorinostat, Figure 1) 11−16 and lead to efficacy in animal models of malaria (compound 2).17 Such findings underscore the potential for Pf HDAC inhibitors to be used for malaria therapy. 18−20 Of the five HDAC encoding genes known in P. falciparum one has homology to mammalian class I isoforms (Pf HDAC1), two are similar class II (Pf HDAC2 and 3) mammalian HDACs, while the remaining two are class III HDACs, or silent information regulator 2 (SIR2) proteins. 19 In light of the close sequence homology between Pf HDAC1 and human class I HDACs 21 an

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“…6. While the bisamide 14 [68] was metabolically not stable, the mono-amides 15 and 16 demonstrated efficacy in a colon cancer xenograft model [69,70].…”

Section: Ketones and Trifluoromethyl Ketonesmentioning

confidence: 99%

The Role of Histone Deacetylases in Neurodegenerative Diseases and Small-Molecule Inhibitors as a Potential Therapeutic Approach

Bürli¹,

Thomas²,

Beaumont

2010

Topics in Medicinal Chemistry

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Neurodegenerative disorders are devastating for patients and their social environment. Their etiology is poorly understood and complex. As a result, there is clearly an urgent need for therapeutic agents that slow down disease progress and alleviate symptoms. In this respect, interference with expression and function of multiple gene products at the epigenetic level has offered much promise, and histone deacetylases play a crucial role in these processes. This review presents an overview of the biological pathways in which these enzymes are involved and illustrates the complex network of proteins that governs their activity. An overview of small molecules that interfere with histone deacetylase function is provided.

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Discovery of a Potent Class I Selective Ketone Histone Deacetylase Inhibitor with Antitumor Activity in Vivo and Optimized Pharmacokinetic Properties

Cited by 42 publications

References 23 publications

The DNA damage mark pH2AX differentiates the cytotoxic effects of small molecule HDAC inhibitors in ovarian cancer cells

The DNA damage mark pH2AX differentiates the cytotoxic effects of small molecule HDAC inhibitors in ovarian cancer cells

Discovery of a Selective Series of Inhibitors of Plasmodium falciparum HDACs

The Role of Histone Deacetylases in Neurodegenerative Diseases and Small-Molecule Inhibitors as a Potential Therapeutic Approach

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