DCAF1-based PROTACs with activity against clinically validated targets overcoming intrinsic- and acquired-degrader resistance.

Journal

Nature communications

ISSN: 2041-1723

Titre abrégé: Nat Commun

Pays: England

ID NLM: 101528555

Informations de publication

Date de publication:
04 Jan 2024

Historique:

received: 12 05 2023

accepted: 05 12 2023

medline: 5 1 2024

pubmed: 5 1 2024

entrez: 4 1 2024

Statut: epublish

Résumé

Targeted protein degradation (TPD) mediates protein level through small molecule induced redirection of E3 ligases to ubiquitinate neo-substrates and mark them for proteasomal degradation. TPD has recently emerged as a key modality in drug discovery. So far only a few ligases have been utilized for TPD. Interestingly, the workhorse ligase CRBN has been observed to be downregulated in settings of resistance to immunomodulatory inhibitory drugs (IMiDs). Here we show that the essential E3 ligase receptor DCAF1 can be harnessed for TPD utilizing a selective, non-covalent DCAF1 binder. We confirm that this binder can be functionalized into an efficient DCAF1-BRD9 PROTAC. Chemical and genetic rescue experiments validate specific degradation via the CRL4

Identifiants

DOI: 10.1038/s41467-023-44237-4 PMID: 38177131

pubmed: 38177131

doi: 10.1038/s41467-023-44237-4

pii: 10.1038/s41467-023-44237-4

doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

Pagination

275

Subventions

Organisme : EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)

ID : 884331

Organisme : Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (Swiss National Science Foundation)

ID : 310030_301206

Organisme : Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (Swiss National Science Foundation)

ID : CRSII5_186230

Organisme : Verein fur Krebsforschung (Association for Cancer Research)

ID : KFS 4980-02-2020

Informations de copyright

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