%0 Journal Article
%T Discovery of TCP-(MP)-caffeic acid analogs as a new class of agents for treatment of osteoclastic bone loss.
%A Chen Z
%A Choi ER
%A Encarnacion AM
%A Yao H
%A Ding M
%A Park YH
%A Choi SM
%A An YJ
%A Hong E
%A Choi HJ
%A Kim SK
%A Nam YE
%A Kim GJ
%A Park SW
%A Kim JS
%A Kim E
%A Lee S
%A Cho JH
%A Lee TH
%J Bioorg Chem
%V 150
%N 0
%D 2024 Sep 1
%M 38968905
%F 5.307
%R 10.1016/j.bioorg.2024.107603
%X 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.