PDF(Pubmed)
Abstract：
Activin receptor-like kinases 1-7 (ALK1-7) regulate a complex network of SMAD-independent as well as SMAD-dependent signaling pathways. One of the widely used inhibitors for functional investigations of these processes, in particular for bone morphogenetic protein (BMP) signaling, is LDN-193189. However, LDN-193189 has insufficient kinome-wide selectivity complicating its use in cellular target validation assays. Herein, we report the identification and comprehensive characterization of two chemically distinct highly selective inhibitors of ALK1 and ALK2, M4K2234 and MU1700, along with their negative controls. We show that both MU1700 and M4K2234 efficiently block the BMP pathway via selective in cellulo inhibition of ALK1/2 kinases and exhibit favorable in vivo profiles in mice. MU1700 is highly brain penetrant and shows remarkably high accumulation in the brain. These high-quality orthogonal chemical probes offer the selectivity required to become widely used tools for in vitro and in vivo investigation of BMP signaling.
摘要：
活化素受体样激酶1-7(ALK1-7)调节SMAD非依赖性以及SMAD依赖性信号通路的复杂网络。用于这些过程的功能研究的广泛使用的抑制剂之一，特别是对于骨形态发生蛋白（BMP）信号，是LDN-193189。然而,LDN-193189具有不足的全基因组选择性,使其在细胞靶标验证测定中的使用变得复杂。在这里，我们报道了ALK1和ALK2的两种化学上不同的高选择性抑制剂M4K2234和MU1700及其阴性对照的鉴定和综合特征。我们显示MU1700和M4K2234均通过选择性抑制ALK1/2激酶而有效阻断BMP途径，并在小鼠中表现出有利的体内概况。MU1700是高度脑渗透性的,并且在脑中显示出非常高的积累。这些高质量的正交化学探针提供了成为广泛用于体外和体内研究BMP信号传导的工具所需的选择性。
