Hydroxamic acid hybrids: Histone deacetylase inhibitors with anticancer therapeutic potency

Histone deacetylases (HDACs), a class of enzymes responsible for the removal of acetyl functional groups from the lysine residues in the amino-terminal tails of core histones, play a critical role in the modulation of chromatin architecture and the regulation of gene expression. Dysregulation of HDAC expression has been closely associated with the development of various cancers. Histone deacetylase inhibitors (HDACis) could regulate diverse cellular pathways, cause cell cycle arrest, and promote programmed cell death, making them promising avenues for cancer therapy with potent efficacy and favorable toxicity profiles. Hybrid molecules incorporating two or more pharmacophores in one single molecule, have the potential to simultaneously inhibit two distinct cancer targets, potentially overcome drug resistance and minimize drug-drug interactions. Notably, hydroxamic acid hybrids, exemplified by fimepinostat and tinostamustine as potential HDACis, could exert the anticancer effects through induction of apoptosis, differentiation, and growth arrest in cancer cells, representing useful scaffolds for the discovery of novel HDACis. The purpose of this review is to summarize the current scenario of hydroxamic acid hybrids as HDACis with anticancer therapeutic potential developed since 2020 to facilitate further rational exploitation of more effective candidates.