Chemical probes targeting epigenetic proteins: Applications beyond oncology

Abstract

Epigenetic chemical probes are potent, cell-active, small molecule inhibitors or antagonists of specific domains in a protein; they have been indispensable for studying bromodomains and protein methyltransferases. The Structural Genomics Consortium (SGC), comprising scientists from academic and pharmaceutical laboratories, has generated most of the current epigenetic chemical probes. Moreover, the SGC has shared about 4 thousand aliquots of these probes, which have been used primarily for phenotypic profiling or to validate targets in cell lines or primary patient samples cultured in vitro. Epigenetic chemical probes have been critical tools in oncology research and have uncovered mechanistic insights into well-established targets, as well as identify new therapeutic starting points. Indeed, the literature primarily links epigenetic proteins to oncology, but applications in inflammation, viral, metabolic and neurodegenerative diseases are now being reported. We summarize the literature of these emerging applications and provide examples where existing probes might be used.

Keywords: Bromodomain; cardiovascular disease; histone arginine methyltransferase; histone lysine demethylase; histone lysine methyltransferase; inflammation; viral disease.

Figure 1.

Schematic representation of the workflow used to generate epigenetic chemical probes.

Figure 2.

Chemical structure of Epigenetic inhibitors available by the SGC.

Figure 3.

Posttranslational modifications of p65. Schematic representation of p65 subunit of NF-κB primary structure: Rel homology domain, nuclear localization signal (NLS), activation domain (AD), transactivation domain (TAD). Amino acid residues known to be posttranslationally modified are shown; ac (acetylation), ub (ubiquitination), p (phosphorylation), me (methylation), s (symmetric methylation), a (asymmetric methylation).

Figure 4.

Epigenetic regulation of the NF-κB pathway.

Figure 5.

Schematic representation of epigenetic proteins influencing HIV latency.