Proteomics

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Targeted protein degradation reveals BET bromodomains as the cellular target of Hedgehog Pathway Inhibitor-1


ABSTRACT: Target deconvolution of small molecule hits from phenotypic screens presents a major challenge. Illustrative of these are the many screens that have been conducted to find inhibitors for the Hedgehog (Hh) signaling pathway – a major developmental pathway with many implications in health and disease - with many hits but very 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 developed a PROTAC based on the downstream Hedgehog Pathway Inhibitor-1 (HPI-1), a phenotypic screen hit with unknown cellular target. Using our Hedgehog Pathway PROTAC (HPP) we identified and validated BET bromodomains to be the cellular targets of HPI-1. Furthermore, we found that HPP-9 has a unique mechanism of action as a long-acting Hh pathway inhibitor through prolonged BET bromodomain degradation. Collectively, we provide a powerful PROTAC-based approach for target deconvolution, that has answered the longstanding question of the cellular target of HPI-1 and yielded the first PROTAC that acts on the Hh pathway.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Cell Culture

SUBMITTER: Midy Wu  

LAB HEAD: Yibo Wu

PROVIDER: PXD036539 | Pride | 2023-07-20

REPOSITORIES: Pride

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Publications

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

Bagka Meropi M   Choi Hyeonyi H   Héritier Margaux M   Schwaemmle Hanna H   Pasquer Quentin T L QTL   Braun Simon M G SMG   Scapozza Leonardo L   Wu Yibo Y   Hoogendoorn Sascha S  

Nature communications 20230701 1


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  ...[more]

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