Figure 1.

CFFT‐004 rescues F508del‐CFTR function in recombinant FRT epithelia by acting both as a CFTR corrector and as a CFTR potentiator. (A, C) Ussing chamber recordings of I_sc from FRT epithelia expressing F508del‐CFTR acquired at 37°C are shown. Prior to commencing the recordings, in (A), F508del‐CFTR expressing epithelia were treated for 24 h at 37°C with either the vehicle DMSO (0.1% v·v⁻¹), CFFT‐004 (0.1–30 μM) or the CFTR corrector lumacaftor (VX‐809; 3 μM) as indicated, whereas in (C), they were pretreated with lumacaftor (VX‐809; 3 μM) for 24 h at 37°C. In (A) and (C), during the indicated periods, forskolin (Fsk; 10 μM), genistein (Gen; 20 μM) and CFTR_inh‐172 (I172; 20 μM) were added to the solutions bathing the apical and basolateral membranes, and in (C), during the indicated period, either the vehicle DMSO (0.1% v·v⁻¹) or CFFT‐004 (0.03–30 μM) were added to the apical solution as indicated (Cmpd). In both (A) and (C), pre‐forskolin baseline I_sc was subtracted from all I_sc recordings before data were averaged. (B) Relationship between CFFT‐004 concentration and change in I_sc for the peak forskolin response and the CFTR_inh‐172‐sensitive current used to determine EC₅₀ values for CFTR correction and potentiation and CFTR correction alone, respectively. (D) Relationship between CFFT‐004 concentration and normalized maximum acute response following CFFT‐004 addition used to determine the EC₅₀ value for CFTR potentiation. The normalized maximal acute response to CFFT‐004 represents the slope corrected maximal acute response to CFFT‐004 normalized to the forskolin‐stimulated ΔI_sc at the time of CFFT‐004 addition. In (A) and (C), data are means ± SD (n = 2), whereas in (B) and (D), data are means ± SD (n = 4); error bars are smaller than symbol size except where shown. In (B) and (D), the continuous lines show the fit of the Hill equation to mean data using a Hill coefficient (H) of 1.