Targeting Chromatin Readers

Therapies resulting from exploitation of signal transduction targets— largely from the protein kinase target class—are a crowning achievement from the “pregenomic” era of cancer biology and drug discovery. This successful paradigm was based on a gradual progression over 20 years from understanding the role of kinases as oncogenes to their establishment as druggable targets with clinically useful levels of efficacy and selectivity. This foundation has rendered any new potential kinase target in cancer (or other diseases) readily assailable for drug discovery with proven technologies. In the “post-genomic” era, tumor genome sequencing efforts such as the Cancer Genome Atlas are cataloging additional genetic events that cause or sustain human cancers and have identified tractable, novel targets for therapy (e.g., B-RAF-vemurafinib and Alk-crizotinib). Of note, such efforts have clearly shown epigenetic phenomena to be critical for tumor maintenance: a summary of Cancer Genome Atlas efforts to date (B. Vogelstein, NCI Translational Science Meeting, 28 July 2011) revealed that 10 of 12 newly identified oncogenes were directly related to regulation of chromatin function. Chromatin modifiers represent a relatively underexplored area for drug discovery; few potent and selective small-molecule ligands for these targets exist, but the potential of this area to impact therapeutics may rival that of the protein kinase target family. This raises the question of whether we can build a viable approach to establish the clinical utility of these targets in less than the 20 years required for protein kinases. Chromatin is the complex of histone proteins, DNA, and RNA that efficiently packages the genome in an appropriately accessible state within each cell. The state of chromatin, and therefore access to the genetic code, is largely regulated by specific chemical modifications to histone proteins and DNA, as well as the recognition of these marks by other proteins and protein complexes (Figure 1). The chemical modification of chromatin is carried out by families of enzymes that can both “write” (create a posttranslational modification (PTM)) and “erase” (chemically remove) such PTMs. These enzymes include druggable targets such as protein kinases and histone deacetylases, and there is also much recent excitement in the area of inhibitor discovery for protein lysine methyltransferases. Although enzymes are frequently favored as targets for drug discovery because of the precedent for medicinal chemistry success and the ligand design information inherent in the chemical transformations they perform, these chromatin-modifying enzymes also frequently create a binding site for the recruitment of other proteins. Targeting the readers of chromatin PTMs represents a novel emerging area of drug discovery focus that may prove useful in modulating both chromatin state and the activity of epigenetic writers and erasers, which also frequently depend on existing PTMs to recognize their substrates, with a unique pharmacology as compared with enzyme inhibitors.1 We present a summary of recent efforts aimed at modulating the activity of chromatin reader proteins of modified lysine via small-molecule intervention with the goal of highlighting this less precedented landscape of viable epigenetic targets. Figure 1 The basic functional unit of chromatin is the nucleosome, a histone octamer around which DNA is wrapped. Lysine residues on the histone tail are subject to posttranslational modifications including methylation and acetylation (green). Reader proteins ...