Discovery of Orally Available Runt-Related Transcription Factor 3 (RUNX3) Modulators for Anticancer Chemotherapy by Epigenetic Activation and Protein Stabilization

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.