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Human gene expression patterns are controlled and coordinated by the activity of a diverse array of epigenetic regulators, including histone methyltransferases, acetyltransferases, and chromatin remodelers. Deregulation of these epigenetic pathways can lead to genome-wide changes in gene expression, with serious disease consequences. In recent years, research has suggested that cross talk between genomic (i.e., for example, mutations, translocations) and epigenomic factors may drive the etiology of both hematologic malignancies and solid tumors. Current work in translational research seeks to identify epigenetic regulators whose aberrant activity contributes to oncogenesis, including the histone methyltransferases DOT1L and EZH2 and the bromodomain-containing BET family, and to develop drugs that inhibit the aberrant activity of these regulators. Preclinical and clinical studies using small-molecule inhibitors of epigenetic regulators have underscored their value for therapeutic intervention, and these inhibitors can also be used to drive further studies into dissecting the functions of epigenetic factors in normal and cancer cells.

Human gene expression patterns are controlled and coordinated by the activity of a diverse array of epigenetic regulators, including histone methyltransferases, acetyltransferases, and chromatin remodelers. Deregulation of these epigenetic pathways can lead to genome-wide changes in gene expression, with serious disease consequences. In recent years, research has suggested that cross talk between genomic (i.e., for example, mutations, translocations) and epigenomic factors may drive the etiology of both hematologic malignancies and solid tumors. Current work in translational research seeks to identify epigenetic regulators whose aberrant activity contributes to oncogenesis, including the histone methyltransferases DOT1L and EZH2 and the bromodomain-containing BET family, and to develop drugs that inhibit the aberrant activity of these regulators. Preclinical and clinical studies using small-molecule inhibitors of epigenetic regulators have underscored their value for therapeutic intervention, and these inhibitors can also be used to drive further studies into dissecting the functions of epigenetic factors in normal and cancer cells.

A novel and potent azetidinone inhibitor of the lipoprotein-associated phospholipase A2 (Lp-PLA2), i.e. platelet-activating factor acetylhydrolase, is described for the first time. This inhibitor, SB-222657 (Ki = 40±3 nM, kobs/[I] = 6.6×105 M-1·s-1), is inactive against paraoxonase, is a poor inhibitor of lecithin:cholesterol acyltransferase and has been used to investigate the role of Lp-PLA2 in the oxidative modification of lipoproteins. Although pretreatment with SB-222657 did not affect the kinetics of low-density lipoprotein (LDL) oxidation by Cu2+ or an azo free-radical generator as determined by assay of lipid hydroperoxides (LOOHs), conjugated dienes and thiobarbituric acid-reacting substances, in both cases it inhibited the elevation in lysophosphatidylcholine content. Moreover, the significantly increased monocyte chemoattractant activity found in a non-esterified fatty acid fraction from LDL oxidized by Cu2+ was also prevented by pretreatment with SB-222657, with an IC50 value of 5.0±0.4 nM. The less potent diastereoisomer of SB-222657, SB-223777 (Ki = 6.3±0.5 µM, kobs/[I] = 1.6×104 M-1·s-1), was found to be significantly less active in both assays. Thus, in addition to generating lysophosphatidylcholine, a known biologically active lipid, these results demonstrate that Lp-PLA2 is capable of generating oxidized non-esterified fatty acid moieties that are also bioactive. These findings are consistent with our proposal that Lp-PLA2 has a predominantly pro-inflammatory role in atherogenesis. Finally, similar studies have demonstrated that a different situation exists during the oxidation of high-density lipoprotein, with enzyme(s) other than Lp-PLA2 apparently being responsible for generating lysophosphatidylcholine.

The histone methyltransferases are a group of enzymes which catalyze the transfer of a methyl group from the co-factor S-Adenosylmethionine (SAM) to the lysine and arginine residues of histone tails. This post-translational modification is a key event in maintaining gene expression patterns. In recent years, the relationships between aberrant histone methylation patterns and cancer progression have been recognized. These developments, along with an improved understanding of the underlying structural biology, have made histone methyltransferases highly attractive targets for therapeutic intervention. The histone lysine methyltransferase EZH2 (Enhancer of Zeste Homolog 2) is frequently over-expressed in a wide variety of cancerous tissues. There is a strong correlation between overexpression of EZH2 and aberrant transcriptional signaling in cells, ultimately resulting in poor clinical prognosis. Inhibition of EZH2 is expected to alter transcriptional expression and ultimately lead to an improved clinical outcome. This presentation will describe medicinal chemistry efforts in the development of highly potent and selective small molecule inhibitors of EZH2. The synthesis, SAR, and identification of a clinical candidate will be discussed. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2939. doi:1538-7445.AM2012-2939