Fig. 4

E571K XPO1 mutation does not disrupt the biophysical mechanism of action for candidate SINE therapeutics. a 2-dimensional chemical structure of SINE molecules KPT-185 (top), KPT-330 (selinexor; middle), and KPT-8602 (eltanexor; bottom). b 3-dimensional rendering of crystal structures for wildtype- (WT) and E571K-XPO1 bound to SINE molecules KPT-185 (top), KPT-330 (selinexor; middle), and KPT-8602 (eltanexor; bottom). Select XPO1-KPT interactions are shown with dashed lines. Electron density for these structures are shown in the supplemental information. No significant changes to drug-target interactions are observed between wt- and E571K-XPO1. c Proliferation potential of wt or heterozygous XPO1-E571K expressing HEK293 cells upon exposure to SINE molecules KPT-185 (left), KPT-330 (selinexor; middle), and KPT-8602 (eltanexor; right) determined via MTS assay after 48 h. A similar dose-dependent response was observed between both wt and E571K-XPO1 expressing HEK293 cells with each SINE molecule. Proliferation was normalized to the untreated condition. Statistical significance was determined using the Two-stage linear step-up procedure of Benjamini, Krieger and Yekutieli, with Q = 1%. “*” is indicative of p < 0.05, and “***” is indicative of p < 0.001. d Proliferation potential of wt or heterozygous XPO1-E571K expressing human CLL cells upon exposure to clinically relevant SINE molecules KPT-330 (selinexor; left) and KPT-8602 (eltanexor; right) determined via MTS assay after 48 h. A similar dose-dependent response was observed between both wt and E571K-XPO1 expressing CLL cells with each SINE molecule. Each point represents CLL cells from a different patient. Proliferation was normalized to the untreated condition. Statistical significance determined using the Holm-Sidak method, with alpha = 0.05. Each row was analyzed individually, without assuming a consistent SD