Scientific article
Open access

Targeted protein degradation reveals BET bromodomains as the cellular target of Hedgehog pathway inhibitor-1

Published inNature communications, vol. 14, no. 1, 3893
Publication date2023-07-01
First online date2023-07-01

Target deconvolution of small molecule hits from phenotypic screens presents a major challenge. Many screens have been conducted to find inhibitors for the Hedgehog signaling pathway – a developmental pathway with many implications in health and disease – yielding many hits but only few identified cellular targets. We here present a strategy for target identification based on Proteolysis-Targeting Chimeras (PROTACs), combined with label-free quantitative proteomics. We develop a PROTAC based on Hedgehog Pathway Inhibitor-1 (HPI-1), a phenotypic screen hit with unknown cellular target. Using this Hedgehog Pathway PROTAC (HPP) we identify and validate BET bromodomains as the cellular targets of HPI-1. Furthermore, we find that HPP-9 is a long-acting Hedgehog pathway inhibitor through prolonged BET bromodomain degradation. Collectively, we provide a powerful PROTAC-based approach for target deconvolution, that answers the longstanding question of the cellular target of HPI-1 and yields a PROTAC that acts on the Hedgehog pathway.

  • Protein Domains
  • Proteolysis
  • Antineoplastic Agents
  • Hedhegog Proteins
  • Proteolysis Targeting Chimera
Citation (ISO format)
BAGKA, Meropi et al. Targeted protein degradation reveals BET bromodomains as the cellular target of Hedgehog pathway inhibitor-1. In: Nature communications, 2023, vol. 14, n° 1, p. 3893. doi: 10.1038/s41467-023-39657-1
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ISSN of the journal2041-1723

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