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

Panobinostat (1) inhibits Zn(II)-dependent histone deacetylases (HDACs) which are validated cancer targets. Three sets of 1 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 1 analogues (IC₅₀ range: 150–3320 nM) were less potent HDAC2 inhibitors than 1 (IC₅₀ = 5 nM). Ensemble docking showed that the carboxamide NH₂ group in the most potent 1 analogues S-3 (IC₅₀ = 150 nM) and S-2 (IC₅₀ = 350 nM) enabled hydrogen bond formation with E103 and D104. The proximity of the electron withdrawing carboxamide to the secondary amine in the 1 analogues reduced calculated pK_a values, compared to 1. Reduced electrostatic binding capacity of the 1 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.