Fig. 1: Dose-dependent activation of wildtype CFTR in FRT cells by two HDCF analogs (HDCF104 and uHTS159). | npj Drug Discovery

Fig. 1: Dose-dependent activation of wildtype CFTR in FRT cells by two HDCF analogs (HDCF104 and uHTS159).

From: A novel drug series optimized to address cystic fibrosis and other CFTR deficiency diseases of human airways

Fig. 1: Dose-dependent activation of wildtype CFTR in FRT cells by two HDCF analogs (HDCF104 and uHTS159).The alternative text for this image may have been generated using AI.

Ussing chamber analysis of Fischer rat thyroid (FRT) cells shows stimulation of WT CFTR. a, b Escalating doses of HDCF104 demonstrate strong WT CFTR activity with EC50 = 101 μM (95% CI 91.7 μM to 112.3 μM) as judged by dose-dependence profile. In similar fashion, (c, d) uHTS159 displays robust enhancement of WT CFTR with EC50 = 14.4 μM (95% CI 12.5 μM−17.2 μM). Data is representative of 3 biological replicates and expressed as mean ± SD. Maximal stimulation of wildtype CFTR by saturating concentrations of forskolin in this model is 300−500 μA/cm2. Amiloride (100 µM) was added to block epithelial sodium channels; forskolin (5 µM) augments cellular cAMP and activates CFTR by PKA-dependent phosphorylation of the regulatory domain; inh-172 (10 µM) is a CFTR inhibitor. e Structures of the compounds. Statistics were by use of GraphPad Prism 10 software with the function of Sigmoidal, 4PL, with X as concentration. “HDCF” denotes the medicinal chemistry laboratory in which new compounds were synthesized (directed by Dr. Huw Davies). Panels (a, c) plotted with Microsoft Excel; (b, d) plotted (and compound EC50 calculated) using GraphPad Prism 10 software; Panel (e) created with ChemDraw; panels arranged and presented using Affinity Designer software.

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