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. 2018;16(5):618-626.
doi: 10.2174/1570159X15666170630164226.

KCa3.1 Channel Modulators as Potential Therapeutic Compounds for Glioblastoma

Brandon M Brown  1 , Brandon Pressley  1 , Heike Wulff  1
Affiliations

KCa3.1 Channel Modulators as Potential Therapeutic Compounds for Glioblastoma

Brandon M Brown et al. Curr Neuropharmacol. 2018.

Abstract

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 disease.

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.

Keywords: KCa3.1; NS6180; TRAM-34; glioblastoma; neuroinflammation; repurposing; senicapoc..

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Figures

Fig. (1)
Fig. (1)
Chemical structures of KCa3.1 inhibitors.
Fig. (2)
Fig. (2)
Cartoon illustrating the binding sites of the triarylmethanes TRAM-34 and senicapoc in the inner pore and nifedipine in the fenestration region of KCa3.1. The tetramer of KCa3.1 alpha-subunits is shown as a grey ribbon. The channel associated calmodulin is shown in dark magenta. (The color version of the figure is available in the electronic copy of the article).
See this image and copyright information in PMC

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