Fig. 4.

Selection of resistant mutants in human cells. HCT116 cells were mutagenized and selected for resistance to compound 2. Dose–response validation of 12 resistant clones with identified SEC61A1 mutations against compounds 2 (A) and 1 (B), and against taxol (C). The mean±s.d. of triplicate determinations are shown. The mutations selected here for resistance to compound 2 and of the recently identified mutations by MacKinnon et al. (MacKinnon et al., 2014) conferring resistance to cotransin CT08 [Maifeld et al., 2011; a compound closely related to compound 3 (HUN-7293)] are shown in the stereo model of the human Sec61 complex in in red and gray, respectively. Below, Sec61α1 is shown as a bar with its transmembrane domains numbered. Red, the single mutations; yellow, the double mutation; gray, the mutations shown by MacKinnon et al. (MacKinnon et al., 2014).