TRPM7, a TRP channel with ion conductance and
kinase activities, has emerged as an attractive
drug target for
immunomodulation. Reverse genetics and cell
biological studies have already established a key role for TRPM7 in the inflammatory activation of macrophages. Advancing TRPM7 as a viable molecular target for
immunomodulation requires selective TRPM7 inhibitors with in vivo tolerability and efficacy. Such inhibitors have the potential to interdict inflammatory cascades mediated by systemic and tissue-specialized macrophages.
FTY720, an FDA-approved
drug for
multiple sclerosis inhibits TRPM7. However,
FTY720 is a
prodrug and its metabolite, FTY720-phosphate, is a potent agonist of
sphingosine 1-phosphate (S1P) receptors. In this study, we tested non-phosphorylatable
FTY720 analogs, which are inert against S1PRs and well tolerated in vivo , for activity against TRPM7 and tissue bioavailability. Using patch clamp electrophysiology, we show that
VPC01091.4 and AAL-149 block TRPM7 current at low micromolar concentrations. In culture, they act directly on macrophages to blunt LPS-induced inflammatory
cytokine expression, an effect that is predominantly but not solely mediated by TRPM7. We found that
VPC01091.4 has significant and rapid accumulation in the brain and lungs, along with direct anti-inflammatory action on alveolar macrophages and microglia. Finally, using a mouse model of
endotoxemia, we show
VPC01091.4 to be an efficacious
anti-inflammatory agent that arrests systemic
inflammation in vivo . Together, these findings identify novel small molecule inhibitors that allow TRPM7 channel inhibition independent of
S1P receptor targeting. These inhibitors exhibit potent anti-inflammatory properties that are mediated by TRPM7 and likely other molecular targets that remain to be identified.