Background: The intermediate-conductance Ca2+-activated K+ channel KCa3.1 is widely
expressed in cells of the immune system such as T- and B-lymphocytes, mast cells, macrophages
and microglia, but also found in dedifferentiated vascular smooth muscle cells, fibroblasts and
many cancer cells including pancreatic, prostate, leukemia and glioblastoma. In all these cell types
KCa3.1 plays an important role in cellular activation, migration and proliferation by regulating
membrane potential and Ca2+ signaling.
Methods and Results: KCa3.1 therefore constitutes an attractive therapeutic target for diseases
involving excessive proliferation or activation of one more of these cell types and researchers both
in academia and in the pharmaceutical industry have developed several potent and selective small
molecule inhibitors of KCa3.1. This article will briefly review the available compounds (TRAM-34,
senicapoc, NS6180), their binding sites and mechanisms of action, and then discuss the potential
usefulness of these compounds for the treatment of brain tumors based on their brain penetration
and their efficacy in reducing microglia activation in animal models of ischemic stroke and Alzheimer’s
Conclusion: Senicapoc, which has previously been in Phase III clinical trials, would be available
for repurposing, and could be used to quickly translate findings made with other KCa3.1 blocking
tool compounds into clinical trials.