Fig. 5: Dose-response curves falsify the two-site hypothesis for risdiplam.
From: Specificity, synergy, and mechanisms of splice-modifying drugs
A Two-site hypothesis for risdiplam activity at SMN2 exon 7. Cloud, proteins hypothesized to mediate the effect of risdiplam at the PT of SMN2 exon 7 [hnRNP G (ref. 18) or FUBP1 and KHSRP (ref. 21)]. B PT variants assayed in SMN2 minigenes. C Empirical model for concentration-dependent drug activity; see also Fig. S11. D Schematic illustration of model predictions for the inclusion/exclusion ratio as a function of drug concentration, as well as how model parameters shape this function. E–H Risdiplam titration curves for SMN2 exon 7 minigenes containing (E) the wild-type PT or (F–H) mutated PTs. I–L Branaplam titration curves for SMN2 exon 7 minigenes containing (I) the wild-type PT or (J–L) mutated PTs. Dots and triangles, median qPCR measurements of n = 4 technical replicates, shown for n = 3 biological replicates at nonzero drug concentration (dots) or zero drug concentration (triangles). Lines and shaded regions, predictions (median and 95% credible interval) of inferred dose-response curves. \(H\), inferred Hill coefficients (median and 95% credible interval). PT, purine tract.
