Pharmacological modulation of the TRPM7 channel using a natural product derivate 4043

Description TRPM7 is a ubiquitously expressed bifunctional protein with a channel and a C-terminal kinase domain. Its channel represents a major Mg2+-uptake mechanism in mammalian cells and is a key regulator of cell proliferation and immune homeostasis. The kinase domain is relevant for adaptive immunity. Blockage of the channel has a positive pathophysiological effect on cancer, cardiovascular and neurodegenerative diseases. Restricted ion flow through TRPM7 reduces neuronal cell death, cell growth in tumor tissue and atherosclerotic plaque formation. Due to these properties the channel poses a promising pharmacological target and there is a high demand in highly selective and easily accessible modulators. Waixenicin A, a Xenia diterpenoid, was shown to inhibit the channel effectively and selectively. However, its extraction from the soft coral Sarcothelia Edmondsoni and its synthetic production fail to deliver substantial amounts for a broader usage. We analyzed several synthetic derivates of waixenicin A in calcium imaging experiments and characterized promising candidates electrophysiologically via whole-cell patch-clamp measurements. We identified an intermediate derivate of waixenicin A synthesis, as strong inhibitor of TRPM7. Its easier accessibility makes it a powerful tool for pharmacological regulation of TRPM7 and might serve as a model structure for a therapeutic applications in the future. Topic Categories Immune Mechanisms of Human Disease (HUM)