Chromatin Regulatory Targets for Anticancer Therapeutics

Chromatin serves to organize and compact the genome but also functions as a signaling hub for the dynamic regulation of transcriptional programs that control cell type specification. The historical discovery that several pro-differentiation anti-cancer agents target chromatin regulatory enzymes buoyed early interest in developing drugs that modulate chromatin structure and function. Chromatin-based drug discovery has since flourished alongside major advances in discovery chemistry and target selection, producing a rich collection of chemical probes, drugs, and drug candidates targeting chromatin regulatory processes. The substantial growth and maturity of this field over the last several decades provides an opportunity to reflect on the successes and failures associated with translating chromatin regulatory targets into anti-cancer drugs. Taking a target-centric perspective, we discuss the motivation for pursuing specific chromatin regulatory proteins and review the chemistries that enabled small molecule discovery and development. In so doing, we hope to evaluate the strength of these targets, the agents that prosecute them, and the prospects for future efforts in this field.