Walther-Straub Institute of Pharmacology and Toxicology, Faculty of Medicine, Ludwig-Maximilians Universität München, 80336 Munich, Germany.
Int J Mol Sci. 2020 Sep 23;21(19):7017. doi: 10.3390/ijms21197017.
The transient receptor potential cation channel, subfamily M, member 7 (TRPM7) is a ubiquitously expressed membrane protein, which forms a channel linked to a cytosolic protein kinase. Genetic inactivation of TRPM7 in animal models uncovered the critical role of TRPM7 in early embryonic development, immune responses, and the organismal balance of Zn, Mg, and Ca. TRPM7 emerged as a new therapeutic target because malfunctions of TRPM7 have been associated with anoxic neuronal death, tissue fibrosis, tumour progression, and giant platelet disorder. Recently, several laboratories have identified pharmacological compounds allowing to modulate either channel or kinase activity of TRPM7. Among other small molecules, NS8593 has been defined as a potent negative gating regulator of the TRPM7 channel. Consequently, several groups applied NS8593 to investigate cellular pathways regulated by TRPM7. Here, we summarize the progress in this research area. In particular, two notable milestones have been reached in the assessment of TRPM7 druggability. Firstly, several laboratories demonstrated that NS8593 treatment reliably mirrors prominent phenotypes of cells manipulated by genetic inactivation of TRPM7. Secondly, it has been shown that NS8593 allows us to probe the therapeutic potential of TRPM7 in animal models of human diseases. Collectively, these studies employing NS8593 may serve as a blueprint for the preclinical assessment of TRPM7-targeting drugs.
瞬时受体电位阳离子通道亚家族 M，成员 7（TRPM7）是一种广泛表达的膜蛋白，它形成一个与细胞质蛋白激酶相连的通道。在动物模型中 TRPM7 的遗传失活揭示了 TRPM7 在早期胚胎发育、免疫反应和 Zn、Mg 和 Ca 生物体平衡中的关键作用。TRPM7 成为一个新的治疗靶点，因为 TRPM7 的功能障碍与缺氧神经元死亡、组织纤维化、肿瘤进展和巨大血小板障碍有关。最近，几个实验室已经确定了可以调节 TRPM7 通道或激酶活性的药理学化合物。在其他小分子中，NS8593 被定义为 TRPM7 通道的有效负门控调节剂。因此，许多小组应用 NS8593 来研究由 TRPM7 调节的细胞途径。在这里，我们总结了该研究领域的进展。特别是，在评估 TRPM7 的可成药性方面取得了两个显著的里程碑。首先，几个实验室证明，NS8593 处理可靠地反映了通过 TRPM7 遗传失活操纵的细胞的显著表型。其次，已经表明 NS8593 允许我们在人类疾病的动物模型中探究 TRPM7 的治疗潜力。总之，这些使用 NS8593 的研究可以作为 TRPM7 靶向药物临床前评估的蓝图。
