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

Meropi Bagka, Hyeonyi Choi, Margaux Héritier, Hanna Schwaemmle, Quentin T. L. Pasquer, Simon M. G. Braun, Leonardo Scapozza, Yibo Wu and Sascha Hoogendoorn ()
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Meropi Bagka: University of Geneva
Hyeonyi Choi: University of Geneva
Margaux Héritier: University of Geneva
Hanna Schwaemmle: University of Geneva
Quentin T. L. Pasquer: University of Geneva
Simon M. G. Braun: University of Geneva
Leonardo Scapozza: University of Geneva
Yibo Wu: University of Geneva
Sascha Hoogendoorn: University of Geneva

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-39657-1

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