Multifaceted roles of HDAC7 in disease and the evolving chemical toolkit for its modulation

Histone deacetylase 7 (HDAC7) is a key member of the class IIa HDAC subfamily (HDAC4, 5, 7, and 9) that is characterized by a key tyrosine-to-histidine substitution in its active site, a feature that renders these HDACs catalytically inefficient and underscores their versatile roles beyond intrinsic deacetylation. Structurally, HDAC7 is distinguished from its paralogs by its lack of the conserved N-terminal glutamine-rich domain. This combination of functional duality and a unique structural context enables HDAC7 to regulate a vast array of cellular processes. Consequently, its dysregulation is implicated in numerous pathologies, including cancer and autoimmune disorders, establishing it as a compelling therapeutic target. However, effectively and selectively targeting HDAC7 is complicated by its context-dependent biological modes of actions and the high structural homology it shares with other class IIa isoforms. This review first provides a current overview of the multifaceted roles of HDAC7 in human diseases and discusses how its contributions are dictated by the complex interplay between its catalytic and diverse scaffolding functions. We then summarize the recent medicinal chemistry efforts, from the class-selective deacetylase inhibitors to the recently emerged targeted protein degraders that not only achieve superior isoform selectivity but also modulate HDAC7's deacetylase-independent functions. By bridging the functional complexity of HDAC7 with the latest advances in chemical biology tools, we aim to provide a timely summary of the current status of HDAC7 as a druggable target and offer a perspective on strategies guiding the development of next-generation modulators.