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A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response. Histone recognition and large-scale structural analysis of the human bromodomain family. A chemical probe selectively inhibits G9a and GLP methyltransferase activity in cells. Selective inhibition of BET bromodomains. Skip to main content. Chemical Probes for Drug Discovery. Chemical Probes. The resulting overexpression of NSD2, an H3K36 histone methyltransferase, in t 4;14 p16;q32 multiple myeloma leads to increased H3K36me2, genomic disorganization of the H3K36me2, and oncogenic reprogramming 10 — Additionally, it has been shown that the catalytic activity of this histone methyltransferase is essential for its biological role in the NSD2 translocation subpopulation of multiple myeloma Hence, a small-molecule inhibitor of NSD2 may abrogate the oncogenic role of the epigenetic protein in this subpopulation of multiple myeloma.

4th Annual MarketsandMarkets Epigenetics Congress

Beyond these two types of somatic alterations, there are insertions, deletions, and point mutations of unknown biological consequence in epigenetic genes that occur with high frequency Identifying drug targets from these somatic alterations is more difficult, as some will not be critical for tumor growth and survival. Others will have a critical role in tumor biology, but the somatic alteration will result in an inactivation of gene product function.

In these cases, a mechanistic understanding of how inactivation results in epigenetic dysregulation and consequent perturbation of biological function needs to be elucidated. The second requirement is that the inactivation of an epigenetic gene makes the tumor more sensitive to a second druggable target. This is a high requirement for biological validation, but there is early evidence of such an example. These alterations occur with high prevalence in multiple tumor types and they appear to inactivate or alter the chromatin-remodeling function of the complex 14 , Roberts and colleagues have found that SNF5 antagonizes EZH2 in regulating stem cell—associated programs in embryonic stem cells, and that EZH2 is required for the growth of SNF5-deficient malignant rhabdoid tumor cells Consistent with this finding, Pollock and colleagues have reported that a potent selective EZH2 inhibitor induces apoptosis and differentiation in malignant rhabdoid tumor cells, and that dosing of the inhibitor in mice results in regression of xenograft rhabdoid tumors Taken together, an understanding of the interplay between two epigenetic regulators of gene expression SNF5 and EZH2 was essential to design a targeted pharmacological approach for this tumor population with an inactivating somatic mutation.

Indeed, there are quite a number of scientific and pragmatic challenges, many of which are summarized in Table 1. In the absence of these tools, drug discovery scientists are primarily using genetic association as described above combined with molecular tools siRNA, shRNA, overexpression, catalytic-inactive mutants to identify relevant disease targets. However, each of these methods has caveats and is best confirmed with selective pharmacological modulators where available.

The SGC has enabled the public dissemination of a substantial number of epigenetic protein crystal structures helpful for computational approaches in medicinal chemistry and chemical probes, e. From a practical standpoint, building assays to screen compound libraries for small molecule modulators of epigenetic enzymes is not straightforward. In most cases, the initial screen is biochemical and ideally should recapitulate the activity in the cellular context. Many epigenetic targets exist as large complexes of proteins e. As such, screens using apo-enzymes may be misleading and not represent the cellular context.

Substrates may not be canonical histones, as exemplified by SMYD2, where p53 peptide is preferred over histone as a substrate for methylation Another example of assay development complexity is NSD2, in which the enzyme has been reported to exhibit disparate target preferences based on the nature of the substrate provided, and which is likely best assayed using nucleosomes as substrate Cellular assays for epigenetic proteins also have proven to be somewhat complex.

For many epigenetic targets, effects of knockdown or inhibitors in cell culture often take several days to see histone mark changes or effects on target genes, while phenotypic responses may require up to 7 to 10 days to observe e.

Epigenetic Drug Discovery

Translating the cell-based activity to traditional xenograft models will require a relevant sensitive tumor and perhaps longer duration studies to see effects see comments on EZH2 inhibitors below. EZH2 inhibitors.

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EZH2 inhibitor identification efforts at GlaxoSmithKline, among others, were initiated using biochemical assays The PRC2 complex consists of three or five member proteins, and exhibits lysine methyltransferase catalytic activity on peptides, histones, mono-nucleosomes, and oligo-nucleosomes Figure 1 A. Direct EHZ2 inhibitors, those that bind directly to the protein and inhibit its enzyme activity, have been identified through biochemical assays using the PRC2 complex on a variety of substrates 30 , 32 — An additional complexity is that H3K27me3 peptide, the product of the reaction, binds allosterically to PRC2 and increases catalytic activity of the complex.

Interestingly, some EHZ2 inhibitors have been found to possess greater biochemical potency and a longer enzyme-inhibitor residence time when H3K27me3 peptide is bound to PRC2 Optimization of GSK EZH2 inhibitors resulted in the development of GSK 29 , 34 , which possesses potent, highly selective biochemical and cellular on-target potency, assessed by decreases in H3K27 trimethylation. Tumor growth inhibition continues after cessation of drug dosing for 24 days or longer It is noteworthy that the three groups have reported EZH2 inhibitors independently, and all three inhibitor structures are strikingly similar Figure 2.

These successful efforts clearly indicate that EZH2 or PRC2 is a druggable small-molecule target, but the convergent inhibitor structures may indicate that the EZH2 inhibitor-binding pocket all are competitive with the enzyme cofactor S-adenosyl methionine is highly stringent. DOT1L inhibitors. Another histone methyltransferase, DOT1L, appears to be the sole enzyme responsible for catalyzing the methylation of H3K79 MLL is a histone-lysine N-methyltransferase that normally catalyzes the methylation of H3K4, but this function is lost when chromosomal translocations occur that produce oncogenic fusion proteins, e.

Accumulated evidence indicates that, in many of these MLL-rearranged leukemias, DOT1L associates with the fusion protein, is activated and drives development and progression of the disease refs.


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This evidence has made DOT1L a compelling drug target for drug discovery, and several small-molecule inhibitors have subsequently been reported Figure 2 and refs. Because these are developmental disorders, according to Dr. However, research in both animals and humans has linked these same phenotypes, among many other effects, with ingestion of the synthetic chemical bisphenol A BPA through epigenetic effects.

Plenge, such as autism. This identification of the pathways of these phenotypes and not just of the symptoms of the phenotypes should therefore, according to Dr. What is noteworthy, though, is that epigenetics—or even any consideration of epigenetic mechanisms—are not mentioned by Dr.

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That such suffering could be alleviated by the seemingly simple combination of genomics with epigenetics seems incentive enough to pursue the unification of these two fields as recommended here by Dr. Randy Jirtle. Science-based doubts about the results of epigenetic research are understandable enough, and resolvable through science-based back-and-forth; the non-science based opprobrium directed towards epigenetics is not so understandable.

Hopefully posts like this contribute to this project. Is the unification of epigenetics and genomics possible? Is it probable? What would have to occur for this unification to take place?

Or is genomics fine without epigenetics and vice versa? Bisphenol A effects on the growing mouse oocyte are influenced by diet. A review of the environmental fate, effects, and exposures of bisphenol A. An extensive new literature concerning low-dose effects of bisphenol A shows the need for a new risk assessment. Environmental health perspectives , ; Watts, M.