骨形态发生蛋白BMP信号通路是调控胚胎发育、组织修复和干细胞命运决定的关键通路其过度激活与骨异位钙化、纤维化及某些肿瘤的发生发展密切相关。LDN-193189DM-3189AbMoleM1873是一种选择性BMP I型受体抑制剂其对ALK2BMPR-I和ALK3BMPR-IA的IC₅₀分别为5 nM和30 nM而对ALK4ActR-IB、ALK5TβR-I等TGF-β家族其他受体的抑制活性低100倍以上[1]。LDN-193189CAS No.1062368-24-4能通过与受体激酶结构域的ATP结合口袋竞争性结合抑制Smad1/5/8的磷酸化及下游靶基因如Id1、Id2、Id3的表达[1]。在干细胞分化的研究中LDN-193189能用于成骨分化、滋养层分化等多个分化方向的调节并在多种细胞分化模型中得到验证。在C2C12成肌细胞中100–500 nM 的LDN-193189可阻断BMP-2诱导的成骨分化恢复肌管形成能力而在小鼠胚胎干细胞中LDN-193189200 nM的处理能抑制BMP-4 诱导的滋养层分化维持多能性标志物Oct4和Sox2的表达[2]。LDN-193189100–250 nM在人间充质干细胞中能抑制成骨分化并促进成脂或成软骨分化方向的转换提示BMP信号在谱系选择中的决定性作用[3]。动物实验中LDN-193189DM-3189在小鼠进行性骨化性纤维发育不良FOP模型中通过腹腔注射3 mg/kg每日一次能显著抑制异位骨化灶的形成LDN-193189DM-3189在肺动脉高压模型中灌胃给药5 mg/kg每日两次能减轻肺血管重塑和右心室肥厚[4]。LDN-193189CAS No.1062368-24-4还被广泛应用于诱导多能干细胞iPSC向神经外胚层或中内胚层的定向分化方案中通过抑制内源性BMP信号维持神经前体细胞的自我更新能力[5]。参考文献及鸣谢[1] Cuny, G. D.; Yu, P. B.; Laha, J. K.; et al. Structure-activity relationship study of bone morphogenetic protein (BMP) signaling inhibitors. Bioorganic Medicinal Chemistry Letters 2008, 18 (15), 4388–4392.[2] Yu, P. B.; Deng, D. Y.; Lai, C. S.; et al. BMP type I receptor inhibition reduces heterotopic ossification. Nature Medicine 2008, 14 (12), 1363–1369.[3] Hao, J.; Daley, G. Q.; Hong, C. C. H. Exploring the differentiation and development of the human nephron with hPSCs. Nature Protocols 2018, 13 (7), 1591–1613.[4] Hiepen, C.; Jatzlau, J.; Hilbig, H.; et al. BMP signaling in the skeleton and the kidney: a shared gatekeeper of tissue homeostasis. Cellular and Molecular Life Sciences 2020, 77 (14), 2749–2766.[5] Chambers, S. M.; Fasano, C. A.; Papapetrou, E. P.; et al. Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling. Nature Biotechnology 2009, 27 (3), 275–280.
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