Fig. 3: HPP-9 acts as a PROTAC for BET bromodomains.

a Principal component analysis of 5343 quantified proteins clearly separates all sample groups. b Volcano plot of log2(fold change) to significance shows the potential direct targets of HPP-9. Blue circles represent all hits overlapping between replicates and red circles with text labels are the most significant hits. c HPP-9 dose-dependently degrades the BET bromodomain proteins, as shown by western blot analysis. Representative blot of three independent experiments. d, e All HPPs were profiled for their ability to degrade BRD2/3/4 by western blot, which revealed (e) a good correlation between Hedgehog pathway inhibition (Fig. 1e, replotted for clarity) and BET bromodomain degradation. Mean ± SEM of three independent experiments is plotted. f Representative immunoblot of a competition experiment between HPP-9 and HPI-1, hydroxythalidomide, and MG-132. Three independent experiments. g HPP-9 is able to degrade BET proteins in medulloblastoma cells MB55 and MB56. Representative immunoblot (MB56) of N = 2 independent experiments for each cell line. Normalized band signal intensities are shown underneath the blots. Source data are provided as a Source Data file.