A novel histone deacetylase 8 (HDAC8)-specific inhibitor PCI-34051 induces apoptosis in T-cell lymphomas

Balasubramanian, Sriram; Ramos, Jason; Luo, Weigang; Sirisawad, Mint; Verner, Erik; Buggy, Joseph J.

doi:10.1038/leu.2008.9

Cited by 410 publications

(387 citation statements)

References 50 publications

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“…We compared the specificity of the active and inactive HDAC inhibitors (Table S2). Although the majority of the inhibitors in our set have known activity against multiple HDAC proteins, making it difficult to identify the specific HDAC target, inhibitors selective for HDAC6 (Tubastatin) (28) and HDAC8 (PCI-34051) (29) did not score in our screen, making it unlikely that either of these HDAC proteins is involved in maintaining aberrant chromatin accessibility in Ewing sarcoma. The overall reproducibility of the screen confirms the robustness of HT-FAIRE as an approach for discovering biologically relevant compounds using a small, focused compound library.…”

Section: Resultsmentioning

confidence: 96%

High-throughput small molecule screen identifies inhibitors of aberrant chromatin accessibility

Pattenden

Simon

Wali

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Mutations in chromatin-modifying proteins and transcription factors are commonly associated with a wide variety of cancers. Through gain-or loss-of-function, these mutations may result in characteristic alterations of accessible chromatin, indicative of shifts in the landscape of regulatory elements genome-wide. The identification of compounds that reverse a specific chromatin signature could lead to chemical probes or potential therapies. To explore whether chromatin accessibility could serve as a platform for small molecule screening, we adapted formaldehyde-assisted isolation of regulatory elements (FAIRE), a chemical method to enrich for nucleosomedepleted genomic regions, as a high-throughput, automated assay. After demonstrating the validity and robustness of this approach, we applied this method to screen an epigenetically targeted small molecule library by evaluating regions of aberrant nucleosome depletion mediated by EWSR1-FLI1, the chimeric transcription factor critical for the bone and soft tissue tumor Ewing sarcoma. As a class, histone deacetylase inhibitors were greatly overrepresented among active compounds. These compounds resulted in diminished accessibility at targeted sites by disrupting transcription of EWSR1-FLI1. Capitalizing on precise differences in chromatin accessibility for drug discovery efforts offers significant advantages because it does not depend on the a priori selection of a single molecular target and may detect novel biologically relevant pathways.chromatin | Ewing sarcoma | high throughput screening | FAIRE | histone deacetylase inhibitor A growing range of human cancers have been associated with mutations in genes encoding proteins that regulate chromatin, the assembly of proteins and DNA that control DNAtemplated processes, including transcription and replication (1, 2). Small molecule drugs and chemical probes offer an approach to explore the biological consequences of these mutations and are emerging as a therapeutic strategy to target disease pathways. Drugs targeting histone deacetylase (HDAC) enzymes, the bromodomain reader BRD4, and DNA methylation have already received regulatory approval or have entered clinical testing, and chemical probes have been developed against a broad range of chromatin regulators, such as the methyltransferases (3) DOT1L (4), EZH2 (5-8), and G9a (9, 10), and the reader proteins L3MBTL3 (11) and BRD4 (12-14). However, transcription factors that lack enzymatic activity or binding pockets with targetable molecular features have been considered "undruggable," and a reductionist approach based on identification of their molecular targets has largely failed.The majority of Ewing sarcomas, highly malignant pediatric bone and soft tissue tumors, harbor a chromosomal translocation that joins the amino-terminal domain of EWSR1 with the DNA binding domain of the ETS transcription factor family member FLI1 to generate the chimeric transcription factor EWSR1-FLI1 (15). Translocations with other ETS genes are detected in most of the remaining tumors, y...

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Section: Resultsmentioning

confidence: 96%

High-throughput small molecule screen identifies inhibitors of aberrant chromatin accessibility

Pattenden

Simon

Wali

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Inhibition of meiotic histone deacetylation has been found to induce aneuploidy in fertilized mouse oocytes, which resulted in embryonic death in utero at an early stage of development (Akiyama et al 2006). Furthermore, it has been shown that treatment with inhibitors of histone deacetylase induced apoptosis of cancer cells and some of such inhibitors have been used as anticancer agents (Cheong et al 2003, Maggio et al 2004, Balasubramanian et al 2008. In summary, it is possible that pyruvate prevents oocyte aging by providing energy for oocyte metabolism and by inhibiting apoptosis.…”

Section: N Liu Y-g Wu and Othersmentioning

confidence: 99%

Pyruvate prevents aging of mouse oocytes

Liu

Wu²,

Lan³

et al. 2009

Reproduction

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Inhibiting oocyte aging is important not only for healthy reproduction but also for the success of assisted reproduction techniques. Although our previous studies showed that cumulus cells accelerated aging of mouse oocytes, the underlying mechanism is unknown. The objective of this paper was to study the effects of pyruvate and cumulus cells on mouse oocyte aging. Freshly ovulated mouse cumulus-oocyte complexes (COCs) or cumulus-denuded oocytes (DOs) were cultured in Chatot-Ziomek-Bavister (CZB) medium or COC-conditioned CZB medium supplemented with different concentrations of pyruvate before being examined for aging signs and developmental potential. Pyruvate supplementation to CZB medium decreased rates of ethanol-induced activation in both COCs and DOs by maintaining their maturation-promoting factor activities, but more pyruvate was needed for COCs than for DOs. Addition of pyruvate to the COC-conditioned CZB also alleviated aging of DOs. Observations on cortical granules, level of BCL2 proteins, histone acetylation, intracellular concentration of glutathione, and embryo development all confirmed that pyruvate supplementation inhibited aging of mouse oocytes. It is concluded that the aging of mouse oocytes, facilitated by culture in COCs, can be partially prevented by the addition of pyruvate to the culture medium.

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“…Letter HDAC1 IC 50 = 4 μM), 15 which is a tool molecule most often utilized to study the effects of HDAC8 inhibition.…”

Section: Acs Medicinal Chemistry Lettersmentioning

confidence: 99%

Development of a Potent and Selective HDAC8 Inhibitor

Ingham

Paranal

Smith

et al. 2016

ACS Med. Chem. Lett.

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A novel histone deacetylase 8 (HDAC8)-specific inhibitor PCI-34051 induces apoptosis in T-cell lymphomas

Cited by 410 publications

References 50 publications

High-throughput small molecule screen identifies inhibitors of aberrant chromatin accessibility

High-throughput small molecule screen identifies inhibitors of aberrant chromatin accessibility

Pyruvate prevents aging of mouse oocytes

Development of a Potent and Selective HDAC8 Inhibitor

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