title: Discovery of Orally Available Runt-Related Transcription Factor 3 (RUNX3) Modulators for Anticancer Chemotherapy by Epigenetic Activation and Protein Stabilization.
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.
authors: †Translational Research Center for Protein Function Control, Department of Biotechnology, Yonsei University, Seodaemun-gu, Seoul 120-749, Republic of Korea.
authors: Jee Sun
authors: JS
authors: Yang
authors: †Translational Research Center for Protein Function Control, Department of Biotechnology, Yonsei University, Seodaemun-gu, Seoul 120-749, Republic of Korea.
authors: Chulho
authors: C
authors: Lee
authors: †Translational Research Center for Protein Function Control, Department of Biotechnology, Yonsei University, Seodaemun-gu, Seoul 120-749, Republic of Korea.
authors: Misun
authors: M
authors: Cho
authors: ⊥Department of Biomedical Sciences (WCU Program), Yonsei University, Seodaemun-gu, Seoul 120-749, Republic of Korea.
authors: Hyuntae
authors: H
authors: Kim
authors: ⊥Department of Biomedical Sciences (WCU Program), Yonsei University, Seodaemun-gu, Seoul 120-749, Republic of Korea.
authors: Jae Hyun
authors: JH
authors: Kim
authors: ⊥Department of Biomedical Sciences (WCU Program), Yonsei University, Seodaemun-gu, Seoul 120-749, Republic of Korea.
authors: Seonghwi
authors: S
authors: Choi
authors: ‡Bioevaluation Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Cheongwon, Chungbuk 363-883, Republic of Korea.
authors: Soo Jin
authors: SJ
authors: Oh
authors: ‡Bioevaluation Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Cheongwon, Chungbuk 363-883, Republic of Korea.
authors: Jong Soon
authors: JS
authors: Kang
authors: §College of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Yeonsu-gu, Incheon 406-840, Republic of Korea.
authors: Jin-Hyun
authors: JH
authors: Jeong
authors: ∥College of Pharmacy, Gachon University of Medicine and Science, Incheon 406-799, Republic of Korea.
authors: Hyun-Jung
authors: HJ
authors: Kim
authors: †Translational Research Center for Protein Function Control, Department of Biotechnology, Yonsei University, Seodaemun-gu, Seoul 120-749, Republic of Korea.|⊥Department of Biomedical Sciences (WCU Program), Yonsei University, Seodaemun-gu, Seoul 120-749, Republic of Korea.
authors: Gyoonhee
authors: G
authors: Han
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D050677:Core Binding Factor Alpha 3 Subunit / Q000737:chemistry* / Q000235:genetics; D044127:Epigenesis, Genetic / Q000187:drug effects; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008861:Microsomes / Q000378:metabolism; D055550:Protein Stability / Q000187:drug effects; D011728:Pyridones / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D050677:Core Binding Factor Alpha 3 Subunit; D056572:Histone Deacetylase Inhibitors; D011728:Pyridones