FIGURE 11.

TMEM16A activity of additional niclosamide analogs and the impact of benchmark antagonists on endogenous calcium-activated chloride currents in the colorectal cancer cell line, COLO205. RNAseq identified several colorectal cancer cell lines as overexpressing TMEM16A (Supplementary Figure 43). Shown are results from QPatch electrophysiology studies indicating COLO205 cells exhibit the characteristic current–voltage relationship of TMEM16A which was sensitive to the TMEM16A antagonists benzbromarone (A), CaCCinh-A01 (B) and 1PBC (C), the later showing the same anomalous effects on the inward current observed with cloned TMEM16A in HEK293 cells. The structure activity relationship of several other niclosamide analogs is provided in (D). Drug repurposing has identified niclosamide as a promising new treatment for cancer, but its mechanism is not fully understood. Mook et al. (2015) have found niclosamide and related molecules suppress signaling and proliferation of cancer cells, including from the colon cancer cell line HCT-116. We find these compounds are also potent TMEM16A antagonists. Our compound numbering (Cpd#), the compound numbering by Mook et al. (2015) (RM#), and the calculated potency (IC₅₀, μM) of the molecules in our TMEM16A halide-sensitive eYFP assay are shown (D).