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

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Title
Discovery of orally available runt-related transcription factor 3 (RUNX3) modulators for anticancer chemotherapy by epigenetic activation and protein stabilization
Author(s)
J S Yang; C Lee; M Cho; H Kim; J H Kim; S Choi; Soo Jin Oh; Jong Soon Kang; J H Jeong; H J Kim; G Han
Bibliographic Citation
Journal of Medicinal Chemistry, vol. 58, no. 8, pp. 3512-3521
Publication Year
2015
Abstract
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.
ISSN
0022-2623
Publisher
Amer Chem Soc
DOI
http://dx.doi.org/10.1021/acs.jmedchem.5b00062
Type
Article
Appears in Collections:
Ochang Branch Institute > Division of Bioinfrastructure > Laboratory Animal Resource Center > 1. Journal Articles
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