Targeting the transient receptor potential‐melastatin‐like 7 (Trpm7) kinase domain with the first inhibitor, inhibited breast cancer cell migration, invasion and tumor metastasis.

TRPM7 (transient receptor potential melastatin 7) is a non‐selective cation channel fused to protein kinase domain at the C‐terminal whose activity is linked to the control of actomyosin contractility. TRPM7 mediates adhesion and migration of breast cancer cells and promotes breast tumor metastasis. The lack of cell‐permeable inhibitors of the kinase domain represents a barrier to understand the kinase function. Herein, we discovered the first small molecule (KD‐1) that targets TRPM7 kinase activity. Mg 2+ starvation, which promotes TRPM7 kinase activity, induces phosphorylation of eEF2. Treatment of Mg 2+ ‐starved HEK293 cells with KD‐1 decreased eEF2 phosphorylation, consistent with TRPM7 kinase activity suppression in‐cells. KD‐1 decreased the binding of Myosin IIB to TRPM7 in HEK293 and MDA‐MB‐231 cells. And when MDA‐MB‐231 cells were treated with increasing doses of KD‐1, no change in cell viability was seen. Interestingly, KD‐1 inhibited MDA‐MB‐231 cells migration and invasion that have been reported to be regulated by TRPM7 kinase activity. Finally, the bioluminescent signals (to assess metastasis) were significantly lower in KD‐1‐treated mice (25 and 50 mg/kg/day) than in mice treated with vehicle control ( P 蠄 0.05, 2‐sided t ‐test.). As a conclusion, inhibition of TRPM7 kinase activity can be a valid approach to reduce or block breast tumor progression and/or metastasis.