{Reference Type}: Journal Article
{Title}: Discovery of TCP-(MP)-caffeic acid analogs as a new class of agents for treatment of osteoclastic bone loss.
{Author}: Chen Z;Choi ER;Encarnacion AM;Yao H;Ding M;Park YH;Choi SM;An YJ;Hong E;Choi HJ;Kim SK;Nam YE;Kim GJ;Park SW;Kim JS;Kim E;Lee S;Cho JH;Lee TH;
{Journal}: Bioorg Chem
{Volume}: 150
{Issue}: 0
{Year}: 2024 Sep 1
{Factor}: 5.307
{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.