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.
摘要：
LSD1的抑制被提出作为用于治疗骨质疏松症的有希望和有吸引力的疗法。这里,我们合成了一系列新的TCP-（MP）-咖啡酸类似物作为潜在的LSD1抑制剂，通过使用TRAP染色测定法评估其对破骨细胞生成的抑制作用，并尝试探索初步的SAR。其中,TCP-MP-CA（11a）在体外和体内均显示破骨细胞性骨丢失，显示与LSD1抑制剂GSK-LSD1相比的体内作用的显著改善。此外,我们阐明了11a及其前体11e通过FAD直接结合LSD1/CoREST复合物抑制LSD1去甲基化活性并影响其下游IκB/NF-κB信号通路的机制，从而调节破骨细胞骨丢失。这些发现表明11a或11e是治疗破骨细胞性骨质流失的潜在新候选者。以及进一步开发用于骨质疏松症诊所治疗用途的TCP-（MP）-咖啡酸类似物的概念。
