Lecture
LIC Lecture - Target elucidation through target degradation: discovery of BET bromodomains as the target of Hedgehog Pathway Inhibitor-1
- Date
- Thursday 19 January 2023
- Time
- Location
-
Gorlaeus Building
Einsteinweg 55
2333 CC Leiden - Room
- DM0.21
Sascha Hoogendoorn -an alumnus from the LIC is a group leader at the University of Geneva where she works on the chemical biology of signalling pathways. Here she uses phenotypic screens in combination with degrader development to target members of the hedgehog pathway.
Abstract
Phenotypic screens are powerful to identify small molecules that act on a biological process of interest, but the elucidation of the cellular target and/or mechanism of action of the hit compounds presents a major challenge. Consequently, hit compounds often do not reach their full potential as pharmacological leads or chemical biology tool compounds.
Exemplary of this, Hedgehog Pathway Inhibitor 1 (HPI-1) was found as a hit in a phenotypic screen for the Hedgehog (Hh) signaling pathway – a major developmental signaling cascade that establishes the embryonic body plan, and dysregulation of which underlies various cancers. HPI-1 robustly inhibits the Hh pathway in a variety of cell lines, downstream of the activator Smoothened, yet its cellular target has remained elusive for many years.
Here, we present the target elucidation of HPI-1 through the design, synthesis, and evaluation of corresponding proteolysis targeting chimeras (Hedgehog Pathway PROTACs, HPPs) coupled with label-free quantitative proteomics. We show that HPP-9 robustly reports on HPI-1 action on various BET bromodomain proteins, epigenetic modulators known to be important for Hedgehog signal transduction, through their degradation. Moreover, HPP-9 is the first example of a PROTAC targeting the Hedgehog pathway, enabling novel pharmacological strategies to combat Hh pathway-driven disease.