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

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  • Meropi Bagka

    (University of Geneva)

  • Hyeonyi Choi

    (University of Geneva)

  • Margaux Héritier

    (University of Geneva
    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
    University of Geneva)

  • Yibo Wu

    (University of Geneva)

  • Sascha Hoogendoorn

    (University of Geneva)

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.

Suggested Citation

  • Meropi Bagka & Hyeonyi Choi & Margaux Héritier & Hanna Schwaemmle & Quentin T. L. Pasquer & Simon M. G. Braun & Leonardo Scapozza & Yibo Wu & Sascha Hoogendoorn, 2023. "Targeted protein degradation reveals BET bromodomains as the cellular target of Hedgehog pathway inhibitor-1," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39657-1
    DOI: 10.1038/s41467-023-39657-1
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    1. Michael Cohen & Anna Kicheva & Ana Ribeiro & Robert Blassberg & Karen M. Page & Chris P. Barnes & James Briscoe, 2015. "Ptch1 and Gli regulate Shh signalling dynamics via multiple mechanisms," Nature Communications, Nature, vol. 6(1), pages 1-12, November.
    2. Ari J. Firestone & Joshua S. Weinger & Maria Maldonado & Kari Barlan & Lance D. Langston & Michael O’Donnell & Vladimir I. Gelfand & Tarun M. Kapoor & James K. Chen, 2012. "Small-molecule inhibitors of the AAA+ ATPase motor cytoplasmic dynein," Nature, Nature, vol. 484(7392), pages 125-129, April.
    3. Eric S. Fischer & Kerstin Böhm & John R. Lydeard & Haidi Yang & Michael B. Stadler & Simone Cavadini & Jane Nagel & Fabrizio Serluca & Vincent Acker & Gondichatnahalli M. Lingaraju & Ritesh B. Tichkul, 2014. "Structure of the DDB1–CRBN E3 ubiquitin ligase in complex with thalidomide," Nature, Nature, vol. 512(7512), pages 49-53, August.
    4. Jussi Taipale & James K. Chen & Michael K. Cooper & Baolin Wang & Randall K. Mann & Ljiljana Milenkovic & Matthew P. Scott & Philip A. Beachy, 2000. "Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine," Nature, Nature, vol. 406(6799), pages 1005-1009, August.
    5. Georg Petzold & Eric S. Fischer & Nicolas H. Thomä, 2016. "Structural basis of lenalidomide-induced CK1α degradation by the CRL4CRBN ubiquitin ligase," Nature, Nature, vol. 532(7597), pages 127-130, April.
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