Perspectives on the Discovery of Small-Molecule Modulators for Epigenetic Processes

Abstract

Epigenetic gene regulation is a critical process controlling differentiation and development, the malfunction of which may underpin a variety of diseases. In this article, we review the current landscape of small-molecule epigenetic modulators including drugs on the market, key compounds in clinical trials, and chemical probes being used in epigenetic mechanistic studies. Hit identification strategies for the discovery of small-molecule epigenetic modulators are summarized with respect to writers, erasers, and readers of histone marks. Perspectives are provided on opportunities for new hit discovery approaches, some of which may define the next generation of therapeutic intervention strategies for epigenetic processes.

Shifting from the single to the multitarget paradigm in drug discovery

“…One of the major challenges of phenotypic screening is the identification of the target(s) of a hit molecule, (i.e. target deconvolution) and the elucidation of the mode of action [21–23]. Nonetheless, phenotypic screening is valuable for identifying hit compounds for complex processes, such as epigenetic modulation [21].…”

Targeting transcription regulation in cancer with a covalent CDK7 inhibitor

“…However, the transcriptional machinery contains various enzymatic co-factors that can be targeted for development of new therapeutic candidates 3 , including cyclin-dependent kinases (CDKs) 4 . Here we present the discovery and characterization of the first covalent CDK7 inhibitor, THZ1, which has the unprecedented ability to target a remote cysteine residue located outside of the canonical kinase domain, providing an unanticipated means of achieving selectivity for CDK7.…”

Development of Multiple Cell-Based Assays for the Detection of Histone H3 Lys27 Trimethylation (H3K27me3)

“…6 Inhibition of histone lysine methyltransferases such as EZH2 can decrease the level of H3K27me3; thus, these methyltransferases constitute a novel class of drug target for cancer therapeutics. 9 A recent study supported this concept by reporting that a small-molecule EZH2 inhibitor, GSK126, may provide a treatment option for EZH2 mutant lymphoma. 10 Multiple biochemical assays have been reported in the drug discovery effort for small-molecule inhibitors against different epigenetic enzymes.…”