Structure-Guided Development of Selective HDAC4 and HDAC7 Inhibitors That Modulate Th17 Cell Transcription

Abstract Class IIa histone deacetylases (HDACs) are attractive therapeutic targets due to their specialized regulatory functions and restricted expression patterns. Recent studies identified HDAC4 and HDAC7 as critical regulators of Th17-cell differentiation, acting through distinct transcriptional mechanisms to promote Th17 lineage commitment. Building on these findings, we designed, synthesized, and characterized a series of selective HDAC4/7 inhibitors derived from the Class IIa scaffold TMP269. Structure-guided optimization of the metal-proximal and hydrophobic-binding regions generated analogs with improved potency and enhanced isoform selectivity. Luciferase-based transcriptional assays, protein-binding studies, and molecular docking analyses revealed distinct structure–activity relationships that govern HDAC4 versus HDAC7 selectivity. Several compounds exhibited potent and selective inhibition of HDAC4- or HDAC7-dependent transcriptional activity, providing valuable chemical probes to dissect the individual functions of these enzymes in Th17 biology. These next-generation inhibitors establish a foundation for developing targeted therapies for Th17-driven inflammatory disorders, including inflammatory bowel disease.