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

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

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: jsunkim@chonnam.ac.kr.
  • 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: jhcho1@dau.ac.kr.
  • 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: thlee83@jnu.ac.kr.
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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