Discovery of orally available runt-related transcription factor 3 (RUNX3) modulators for anticancer chemotherapy by epigenetic activation and protein stabilization

Jee Sun Yang, Chulho Lee, Misun Cho, Hyuntae Kim, Jae Hyun Kim, Seonghwi Choi, Soo Jin Oh, Jong Soon Kang, Jin Hyun Jeong, Hyun Jung Kim, Gyoonhee Han

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4 Citations (Scopus)


Recently, we identified a novel strategy for anticancer chemotherapy by restoring runt-related transcription factor 3 (RUNX3) levels via lactam-based histone deacetylase (HDAC) inhibitors that stabilize RUNX3. Described here are the synthesis, biological evaluation, and pharmacokinetic evaluation of new synthetic small molecules based on pyridone-based HDAC inhibitors that specifically stabilize RUNX3 by acetylation and regulate its function. Many of the newly synthesized compounds showed favorable RUNX activities, HDAC inhibitory activities, and inhibitory activities on the growth of human cancer cell lines. Notably, one of these new derivatives, (E)-N-hydroxy-3-(2-oxo-1-(quinolin-2-ylmethyl)-1,2-dihydropyridin-3-yl)acrylamide (4l), significantly restored RUNX3 in a dose-dependent manner and showed high metabolic stability, a good pharmacokinetic profile with high oral bioavailability and long half-life, and strong antitumor activity. This study suggests that pyridone-based analogues modulate RUNX3 activity through epigenetic regulation as well as strong transcriptional and post-translational regulation of RUNX3 and could be potential clinical candidates as orally available RUNX3 modulators for the treatment of cancer.

Original languageEnglish
Pages (from-to)3512-3521
Number of pages10
JournalJournal of Medicinal Chemistry
Issue number8
Publication statusPublished - 2015 Apr 23


All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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