Discovery of TCP-(MP)-caffeic acid analogs as a new class of agents for treatment of osteoclastic bone loss

  • Bioorg Chem. 2024 Sep:150:107603. doi: 10.1016/j.bioorg.2024.107603.
Zhihao Chen  1 ,  Eun Rang Choi  2 ,  Alessandra Marie Encarnacion  3 ,  Hongyuan Yao  3 ,  Mina Ding  1 ,  Young-Hoon Park  4 ,  Se Myeong Choi  2 ,  Yeon Jin An  2 ,  Eunmi Hong  4 ,  Hye-Ji Choi  5 ,  Sang Kyoon Kim  6 ,  Ye Eun Nam  2 ,  Geun-Joong Kim  5 ,  Sang-Wook Park  1 ,  Jeong-Sun Kim  7 ,  Eunae Kim  8 ,  Sunwoo Lee  9 ,  Jong Hyun Cho  10 ,  Tae-Hoon Lee  11
Affiliations
  • 1. Department of Oral Biochemistry, Dental Science Research Institute, School of Dentistry, Chonnam National University, Gwangju 61186, Republic of Korea.
  • 2. Department of Medicinal Biotechnology, College of Health Sciences, Dong-A University, Busan 49315, Republic of Korea.
  • 3. Department of Interdisciplinary Program of Biomedical Engineering, Graduate School of Dentistry, Chonnam National University, Gwangju 61186, Republic of Korea.
  • 4. New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, 41061, Republic of Korea.
  • 5. Department of Biological Sciences and Research Center of Ecomimetics, College of Natural Sciences, Chonnam National University, Gwangju 61186, Republic of Korea.
  • 6. Preclinical Research Center (PRC), Daegu-Gyeongbuk Medical Innovation Foundation (K-MEDI Hub), Daegu 41061, Republic of Korea.
  • 7. Department of Chemistry, Chonnam National University, Gwangju 61186, Republic of Korea. Electronic address: [email protected].
  • 8. Department of Pharmacy, College of Pharmacy, Chosun University, Gwangju 61452, Republic of Korea.
  • 9. Department of Chemistry, Chonnam National University, Gwangju 61186, Republic of Korea.
  • 10. Department of Medicinal Biotechnology, College of Health Sciences, Dong-A University, Busan 49315, Republic of Korea; Department of Translational Biomedical Sciences, Graduate School of Dong-A University, Busan 49201, Republic of Korea. Electronic address: [email protected].
  • 11. Department of Oral Biochemistry, Dental Science Research Institute, School of Dentistry, Chonnam National University, Gwangju 61186, Republic of Korea; Department of Interdisciplinary Program of Biomedical Engineering, Graduate School of Dentistry, Chonnam National University, Gwangju 61186, Republic of Korea. Electronic address: [email protected].
PMID: 38968905 DOI: 10.1016/j.bioorg.2024.107603
Abstract

Inhibition of LSD1 was proposed as promising and attractive therapies for treating osteoporosis. Here, we synthesized a series of novel TCP-(MP)-Caffeic acid analogs as potential LSD1 inhibitors to assess their inhibitory effects on osteoclastogenesis by using TRAP-staining assay and try to explore the preliminary SAR. Among them, TCP-MP-CA (11a) demonstrated osteoclastic bone loss both in vitro and in vivo, showing a significant improvement in the in vivo effects compared to the LSD1 inhibitor GSK-LSD1. Additionally, we elucidated a mechanism that 11a and its precursor that 11e directly bind to LSD1/CoREST complex through FAD to inhibit LSD1 demethylation activity and influence its downstream IκB/NF-κB signaling pathway, and thus regulate osteoclastic bone loss. These findings suggested 11a or 11e as potential novel candidates for treating osteoclastic bone loss, and a concept for further development of TCP-(MP)-Caffeic acid analogs for therapeutic use in osteoporosis clinics.

Keywords
Cofactor derivatization; Crystal structure; LSD1/CoREST; Osteoclastogenesis; TCP-(MP)-caffeic acid.
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