Histonetargeted

Histone-targeted refers to therapeutic and research strategies that aim to modulate histones or their post-translational modifications to influence chromatin structure and gene expression. Histones are the core proteins around which DNA is wound to form nucleosomes; their modifications, including acetylation, methylation, phosphorylation, and ubiquitination, help regulate access to genetic information and control cellular processes.

Targets in histone targeting include histone-modifying enzymes (writers that add marks, erasers that remove marks) and histone-binding proteins that recognize specific marks, known as readers. Writers and erasers include histone acetyltransferases and deacetylases, as well as methyltransferases and demethylases. Readers include bromodomain-containing proteins that interpret acetylation marks. Therapeutic efforts also explore histone chaperones and histone variants that influence nucleosome dynamics.

Approaches in histone targeting encompass small-molecule inhibitors, peptides, and degrader technologies. Examples of established or influential modalities include histone deacetylase inhibitors, which are approved for certain lymphomas and other cancers, and EZH2 inhibitors that target a key methyltransferase involved in gene silencing. Bromodomain inhibitors (BET inhibitors) have been widely studied in clinical trials for cancer and other diseases. More recently, targeted protein degradation approaches (PROTACs) and epigenome editing strategies using programmable nucleases fused to histone modifiers have been explored to achieve precise chromatin modulation.

Applications of histone-targeted strategies are broadly focused on oncology, with ongoing research into neurodegenerative and inflammatory diseases. Challenges include achieving selectivity among closely related enzymes, managing toxicity, and addressing redundancy in histone modification networks. The field continues to evolve as new targets, molecules, and delivery approaches emerge.