Trivalent PROTACs enhance protein degradation via combined avidity and cooperativity.
Journal
Nature chemical biology
ISSN: 1552-4469
Titre abrégé: Nat Chem Biol
Pays: United States
ID NLM: 101231976
Informations de publication
Date de publication:
11 2021
11 2021
Historique:
received:
26
11
2020
accepted:
10
08
2021
pubmed:
23
10
2021
medline:
11
11
2021
entrez:
22
10
2021
Statut:
ppublish
Résumé
Bivalent proteolysis-targeting chimeras (PROTACs) drive protein degradation by simultaneously binding a target protein and an E3 ligase and forming a productive ternary complex. We hypothesized that increasing binding valency within a PROTAC could enhance degradation. Here, we designed trivalent PROTACs consisting of a bivalent bromo and extra terminal (BET) inhibitor and an E3 ligand tethered via a branched linker. We identified von Hippel-Lindau (VHL)-based SIM1 as a low picomolar BET degrader with preference for bromodomain containing 2 (BRD2). Compared to bivalent PROTACs, SIM1 showed more sustained and higher degradation efficacy, which led to more potent anticancer activity. Mechanistically, SIM1 simultaneously engages with high avidity both BET bromodomains in a cis intramolecular fashion and forms a 1:1:1 ternary complex with VHL, exhibiting positive cooperativity and high cellular stability with prolonged residence time. Collectively, our data along with favorable in vivo pharmacokinetics demonstrate that augmenting the binding valency of proximity-induced modalities can be an enabling strategy for advancing functional outcomes.
Identifiants
pubmed: 34675414
doi: 10.1038/s41589-021-00878-4
pii: 10.1038/s41589-021-00878-4
pmc: PMC7611906
mid: EMS132536
doi:
Substances chimiques
Ubiquitin-Protein Ligases
EC 2.3.2.27
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1157-1167Subventions
Organisme : Wellcome Trust (Wellcome)
ID : 100476/Z/12/Z
Organisme : Wellcome Trust (Wellcome)
ID : 094090/Z/10/Z
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/N0123735/1
Pays : United Kingdom
Organisme : European Research Council
ID : 311460
Pays : International
Informations de copyright
© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.
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