Advances in the validation of TRPM7 as a drug target using natural products – Update on waixenicin A

TRPM7 is a ubiquitously expressed divalent cation channel that plays an important role in cell adhesion and migration. TRPM7-dependence on the growth and metastasis of some cancers points to TRPM7 as a potential anti-cancer target. Conversely, in brain ischemia models, dysfunctional activity and up regulation of TRPM7 sustains Ca²⁺ overload in neurons leading to cell death, which implicates TRPM7 inhibition as a potential target for stroke therapy. Motivated by the lack of selective inhibitors, we developed and optimization of a high throughput bioassay (J. Biomol. Screen. 2010, 15, 498 – 507) that led to the isolation of waixenicin A, a diterpene from Sarcothelia edmondsoni, as a selective and potent inhibitor of TRPM7. In patch clamp experiments, waixenicin A demonstrated Mg²⁺-dependent inhibition of TRPM7 currents in native cells (J. Biol. Chem. 2011, 286, 39328), while further chemical investigation of the soft coral provided active and inactive analogues that revealed a preliminary SAR.

Since this recent work, waixenicin A has been employed in numerous on-going in vitro and in vivo studies aimed at better understanding the functions of TRPM7, particularly in the context of cancer. Most notably, collaborators at the Netherland Cancer Institute (Cell Calcium 2013, 54, 404) demonstrated that inhibition of TRPM7 by waixenicin A disrupts invadosomes in neuroblastoma cells, a mechanism that appears consistent with the prognosis of TRPM7 expression for breast cancer metastasis and recurrence. Future investigations will seek to assess TRPM7 inhibition in animal tumor and ischemia models. The development of waixenicin A as a successful probe for studying TRPM7's biological functions further demonstrates the value of natural product pharmacophores in advancing new targets for the treatment of disease.