TRPM7 (transient receptor potential melastatin 7) encodes a calcium permeable non-selective cation channel implicated in cell adhesion and magnesium homoeostasis. The TRPM7 gene encodes for a protein kinase whose activity is linked to the control of actomyosin contractility. TRPM7 mediates adhesion and migration of MDA-MB-231 breast cancer cells and recently has been reported to promote breast tumor cell metastasis. The lack of cell-permeable pharmacological inhibitors of the kinase domain represents a barrier to fully understanding kinase function. Herein, we describe the discovery of several compounds that target TRPM7 kinase activity and which were shown to decrease the binding of Myosin IIB to TRPM7 in HEK293 cells and MDA-MB-231 breast cancer cells transfected with pCMV6-TRPM7. Interestingly, two of the inhibitors potently inhibited MDA-MB-231 breast cancer cells migration that has been reported to be regulated by TRPM7 kinase activity. Finally, magnesium starvation, which promotes TRPM7 kinase activity, induces phosphorylation of eEF2. Treatment of cells with several of the compounds decreased eEF2 phosphorylation under conditions of magnesium starvation, consistent with the notion that they inhibit TRPM7 kinase activity in cells.

Discovery of transient receptor potential-melastatin-like 7 (Trpm7) kinase activity inhibitors that inhibit breast cancer cell migration

247th National Meeting (2014)

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