Carboxamide-Bearing Panobinostat Analogues Designed To Interact with E103-D104 at the Cavity Opening of Class I HDAC Isoforms

Panobinostat (<b>1</b>) inhibits Zn(II)-dependent histone deacetylases (HDACs) which are validated cancer targets. Three sets of <b>1</b> analogues containing carboxamide groups designed to form hydrogen bonds with acidic residues (E103, D104) in the cavity opening of a subset of class I isoforms were synthesized and evaluated against HDAC2. All <b>1</b> analogues (IC₅₀ range: 150–3320 nM) were less potent HDAC2 inhibitors than <b>1</b> (IC₅₀ = 5 nM). Ensemble docking showed that the carboxamide NH₂ group in the most potent <b>1</b> analogues <i>S</i>-<b>3</b> (IC₅₀ = 150 nM) and <i>S</i>-<b>2</b> (IC₅₀ = 350 nM) enabled hydrogen bond formation with E103 and D104. The proximity of the electron withdrawing carboxamide to the secondary amine in the <b>1</b> analogues reduced calculated p<i>K</i>_a values, compared to <b>1</b>. Reduced electrostatic binding capacity of the <b>1</b> analogues, together with solvation and steric penalties, was proposed to negate the binding energy benefit of increased hydrogen bonding. Ensemble docking suggested isoform selectivity as unlikely.