Discovery of Pyridone‐Based Histone Deacetylase Inhibitors: Approaches for Metabolic Stability

Histone deacetylases (HDACs) are important enzymes in epigenetic regulation and are therapeutic targets for cancer. Most zinc‐dependent HDACs induce proliferation, dedifferentiation, and anti‐apoptotic effects in cancer cells. We designed and synthesized a new series of pyridone‐based HDAC inhibitors that have a pyridone ring in the core structure and a conjugated system with an olefin connecting the hydroxamic acid moiety. Consequently, most of the selected pyridone‐based HDAC inhibitors showed similar or higher inhibition profiles in addition to remarkable metabolic stability against hydrolysis relative to the corresponding lactam‐based HDAC inhibitors. Furthermore, the selectivity of the novel pyridine‐based compounds was evaluated across all of the HDAC isoforms. One of these compounds, (E)‐N‐hydroxy‐3‐{1‐3‐(naphthalen‐2‐yl)propyl]‐2‐oxo‐1,2‐dihydropyridin‐3‐yl}acrylamide, exhibited the highest level of HDAC inhibition (IC₅₀=0.07 μM ), highly selective inhibition of class I HDAC1 and class II HDAC6 enzymes, metabolic stability in mouse liver microsomal studies, and effective growth inhibition of various cancer cell lines. Docking studies indicated that a long alkyl linker and bulky hydrophobic cap groups affect in vitro activities. Overall, the findings reported herein regarding pyridone‐based HDAC inhibitors can be used to guide future research efforts to develop new and effective anticancer therapeutics.