Recent progress in synthetic strategies to develop potent, HDAC8-selective, small-molecule inhibitors.

Key players in epigenetic control, the 11 zinc-dependent histone deacetylase (HDAC) enzymes have been affirmed as therapeutic targets, particularly in the discovery of new chemotherapy drugs: currently there are 3 FDA-approved pan-HDAC inhibitors (HDACi's), although these are not without their side effects. It has been rationalized that achieving HDAC isoform-selective inhibitors may yield safer drugs. HDAC8 has recently been validated as a novel target for the treatment of (pediatric) neuroblastoma, and its overexpression has been implicated in a range of other diseases. Herein, we discuss the topology of the HDAC8 active site in the context of inhibitor design, and we present recent progress in the discovery of potent, HDAC8-selective small-molecule inhibitors, with a discussion on the particular structural criteria required. HDACi's largely conform to a canonical pharmacophore model of a capping group connected via a linker to a zinc binding group (ZBG), which is typically a (potentially mutagenic) hydroxamic acid. In particular, for HDAC8-selectivity, the small-molecule should adopt a geometric "L"-shape, which may be accomplished by the linker itself, or the linker and capping group. More recently, HDAC isoform selectivity has been realized with hydroxamic acid surrogates, such as ortho-aminoanilides that yield potent and HDAC1-3-selective (but HDAC8-inactive) inhibitors. Hydrazides have long been utilized as bioisosteres of hydroxamic acids in HDAC inhibitor design, but a recent re-visiting explored the attachment of alkyl groups, and an n-hexyl substituent on the distal, non-acylated nitrogen affords potent and selective HDAC8 inhibitors probably through targeting the foot pocket of the active site; this discovery was observed across three different HDACi scaffolds, and thus appears quite general. α-Aminoketo ZBGs have also demonstrated HDAC8-selectivity, with associated benzylic moieties likewise engaging the foot pocket. We speculate that a re-imagining of the ortho-aminoanilide ZBG through a careful and methodical survey of related moieties, may lead to the discovery of additional HDAC8-selective ZBGs towards the realization of safe, pre-clinical inhibitors. 2025 Elsevier Ltd. All rights reserved.