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.