Improving potency and metabolic stability by introducing an alkenyl linker to pyridine-based histone deacetylase inhibitors for orally available RUNX3 modulators

• Published in: European journal of medicinal chemistry 2017-01, Vol.126, p.997-1010
• Main Authors: Song, Doona, Lee, Chulho, Kook, Yoon Jeong, Oh, Soo Jin, Kang, Jong Soon, Kim, Hyun-Jung, Han, Gyoonhee
• Format: Article
• Language: English
• Subjects: Acetylation; Administration, Oral; Animals; Biological Availability; Cell Line, Tumor; Cell Proliferation - drug effects; Core Binding Factor Alpha 3 Subunit - chemistry; Core Binding Factor Alpha 3 Subunit - metabolism; Drug Stability; Epigenetic control; Female; HDAC inhibition; Histone Deacetylase Inhibitors - chemistry; Histone Deacetylase Inhibitors - metabolism; Histone Deacetylase Inhibitors - pharmacokinetics; Histone Deacetylase Inhibitors - pharmacology; Histone Deacetylases - metabolism; Humans; Mice; Microsomes - metabolism; Protein Stability - drug effects; Protein stabilization; Pyridines - chemistry; Pyridines - metabolism; Pyridines - pharmacokinetics; Pyridines - pharmacology; RUNX3; RUNX3 acetylation; Structure-Activity Relationship; Xenograft Model Antitumor Assays
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2016.11.055

RUNX3, a tumor suppressor, is suppressed in various cancers by abnormal epigenetic changes. Histone deacetylases (HDACs) can deacetylate the lysine residues of RUNX3, followed by degradation via a ubiquitin-mediated pathway. Inhibition of HDAC leads to functional restoration of the RUNX3 protein by epigenetic expression and RUNX3 protein stabilization. We previously reported a series of HDAC inhibitors that restored RUNX3 function. In the present study, we introduced an alkenyl linker group to pyridine-based HDAC inhibitors to improve their potencies and chemical properties. This alkenyl linker made the compounds more rigid, facilitating a better fit than alkyl moieties to the active site of HDAC proteins. Most compounds in this series exhibited potent RUNX activities, HDAC inhibitory activities, and inhibitory activities towards the growth of human cancer cell lines. Notably, one of these derivatives, (E)-3-(1-cinnamyl-2-oxo-1,2-dihydropyridin-3-yl)-N-hydroxyacrylamide (7k), showed excellent properties in a microsomal stability study, in a xenograft study, and in an in vivo pharmacokinetic evaluation. Modulation of RUNX3 therefore results in highly potent and orally available anticancer chemotherapeutic agents. A new series of pyridone-core based HDAC inhibitors were synthesized for anticancer chemotherapy through RUNX3 modulation. [Display omitted] •A new series of RUNX3 modulators showed improved in vitro biological evaluations metabolic stability profiles.•Compounds exhibited a significant in vivo antitumor activity and pharmacokinetic profiles.•Compound 7k could be a highly potent and orally available anticancer agent.