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

Article Article scientifique Article Targeted protein degradation reveals BET bromodomains as the cellular target of Hedgehog pathway inhibitor-1 eng 2023-07-01 2023-07-01 author Bagka Meropi 931672 Département de chimie organique (CHIOR) author Choi Hyeonyi 0009-0003-5188-8871 924359 author Heritier Margaux 0000-0002-8394-0406 835570 Section des sciences pharmaceutiques (FARMA) author Schwaemmle Hanna 965710 Département de médecine génétique et développement (GEDEV) author Pasquer Quentin Titouan Loïc 0000-0001-9355-1271 943942 Département de chimie organique (CHIOR) author Braun Simon 0000-0003-2622-9914 930774 Département de médecine génétique et développement (GEDEV) author Scapozza Leonardo 0000-0003-1079-648X 600318 Section des sciences pharmaceutiques (FARMA) author Wu Yibo 969931 Administration de la faculté des sciences (SIAD) author Hoogendoorn Sascha 0000-0002-1155-8697 917221 Département de chimie organique (CHIOR) 3893 10.1038/s41467-023-39657-1 37393376 2041-1723 https://www.nature.com/articles/s41467-023-39657-1 <p>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.</p> Protein Domains Proteolysis Antineoplastic Agents Hedhegog Proteins Proteolysis Targeting Chimera Dewey 540 Dewey 615 Dewey 576.5 Swiss National Science Foundation Deciphering and Targeting the Cancer Ubiquitylome 186405 CH Programmes Swiss National Science Foundation Inhibitors of cilia and Hedgehog signaling: from phenotype to mechanistic understanding 189246 CH Projects Swiss National Science Foundation Epigenome editing to study chromatin remodeling during brain development 194305 CH Careers 31 Section des sciences pharmaceutiques 17 36 Département de chimie organique 141 135 Département de médecine génétique et développement 21D false 1380 Groupe Hoogendoorn 1357 Régulation de la chromatine dans le développement du cerveau 1031 860 NCCR Chemical Biology Nature communications 14 1 da0346bc-166d-4ab6-bac7-51abec64ab3b Article (Published version) Public Article-scientifique-from-crossref.pdf 2782810 application/pdf CC BY-4.0 a23d117ffad5ae7a7a67a965c38485f4d74431022498aaf784692aff81c7444f 3aca02e4-1145-4171-ad72-9cfc2f2df1c5 Supplemental data Public 41467_2023_39657_MOESM2_ESM(4).docx 13034 application/vnd.openxmlformats-officedocument.wordprocessingml.document f78cb5c0acf33b5d6907f2c239a1f84f5742ed1e93fb879ed6d4008b63703a81 3999388a-7b6f-47d1-8160-9bfdbe125136 Supplemental data Public Copie de 41467_2023_39657_MOESM3_ES.xlsx 2376868 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet d521d4ee5c2b4fc3de6c3614cf402131545386431dd4d012f813a676464016cb 15be17ce-d8b5-411d-97b5-0aca4c373740 Supplemental data Public Copie de 41467_2023_39657_MOESM4_ES.xlsx 1128950 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet 33f5427e20dafe750a40ffe38ae4c7d531fe239ad52aab2e29e784170b27a2ce 80ce6aa4-a978-41f4-910f-f7fb66dec4fe Supplemental data Public Copie de 41467_2023_39657_MOESM5_ES.xlsx 29003543 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet adda89f971498552f4b565e78340937bb61153835627960bda1157c009de15ea bba9c996-fe96-478b-b743-58c73954fe4a Supplemental data Public Copie de 41467_2023_39657_MOESM7_ES.xlsx 22373474 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet b2d1db8071e9f57fa83f333da07690f1da1c44917d955209ec5d52abe37ceb4b openAccess Faculté des sciences / Section des sciences pharmaceutiques Faculté des sciences / Section de chimie et biochimie / Département de chimie organique Faculté de médecine / Section de médecine fondamentale / Département de médecine génétique et développement

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Targeted protein degradation reveals BET bromodomains as the cellular target of Hedgehog pathway inhibitor-1	Nature communications			2023	33	26

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Schwaemmle, Hanna