The Hedgehog (Hh) signaling pathway is pivotal for embryonic development of vertebrates and its abnormal activation can lead to tumorigenesis. The current Hh signaling pathway inhibitors target primarily upstream at the level of SMO and they suffer from acquired resistance rendering essential to find new inhibitors with a different mode of action. Hyman et al in 2009 reported 4 different inhibitors from a high throughput screen, Hedgehog Pathway Inhibitors (HPI) 1-4 that act downstream of SUFU. However, the target of HPI-1 was never validated, and it was referred to as GLI antagonist.

To reveal the molecular target of HPI-1 an approach based on targeted protein degradation was introduced in conjunction with label-free quantitative proteomics. Utilizing a Hedgehog Pathway Proteolysis-Targeting Chimera (PROTAC) named HPP, which is a dual-functional compound combining HPI-1 with a cereblon (CRBN) ligand, BET bromodomains were uncovered as the specific targets of HPI-1.