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

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

  • J Med Chem. 2015 Apr 23;58(8):3512-21. doi: 10.1021/acs.jmedchem.5b00062.
Jee Sun Yang 1,  Chulho Lee 1,  Misun Cho 1,  Hyuntae Kim 2,  Jae Hyun Kim 2,  Seonghwi Choi 2,  Soo Jin Oh 3,  Jong Soon Kang 3,  Jin-Hyun Jeong 4,  Hyun-Jung Kim 5,  Gyoonhee Han 1 2
Affiliations

Affiliations

  • 1 †Translational Research Center for Protein Function Control, Department of Biotechnology, Yonsei University, Seodaemun-gu, Seoul 120-749, Republic of Korea.
  • 2 ⊥Department of Biomedical Sciences (WCU Program), Yonsei University, Seodaemun-gu, Seoul 120-749, Republic of Korea.
  • 3 ‡Bioevaluation Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Cheongwon, Chungbuk 363-883, Republic of Korea.
  • 4 §College of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Yeonsu-gu, Incheon 406-840, Republic of Korea.
  • 5 ∥College of Pharmacy, Gachon University of Medicine and Science, Incheon 406-799, Republic of Korea.
PMID: 25811792 DOI: 10.1021/acs.jmedchem.5b00062
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.

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