Proteolysis-targeting chimeras with reduced off-targets.
Journal
Nature chemistry
ISSN: 1755-4349
Titre abrégé: Nat Chem
Pays: England
ID NLM: 101499734
Informations de publication
Date de publication:
18 Dec 2023
18 Dec 2023
Historique:
received:
23
12
2021
accepted:
13
10
2023
medline:
19
12
2023
pubmed:
19
12
2023
entrez:
18
12
2023
Statut:
aheadofprint
Résumé
Proteolysis-targeting chimeras (PROTACs) are molecules that induce proximity between target proteins and E3 ligases triggering target protein degradation. Pomalidomide, a widely used E3 ligase recruiter in PROTACs, can independently degrade other proteins, including zinc-finger (ZF) proteins, with vital roles in health and disease. This off-target degradation hampers the therapeutic applicability of pomalidomide-based PROTACs, requiring development of PROTAC design rules that minimize off-target degradation. Here we developed a high-throughput platform that interrogates off-target degradation and found that reported pomalidomide-based PROTACs induce degradation of several ZF proteins. We generated a library of pomalidomide analogues to understand how functionalizing different positions of the phthalimide ring, hydrogen bonding, and steric and hydrophobic effects impact ZF protein degradation. Modifications of appropriate size on the C5 position reduced off-target ZF degradation, which we validated through target engagement and proteomics studies. By applying these design principles, we developed anaplastic lymphoma kinase oncoprotein-targeting PROTACs with enhanced potency and minimal off-target degradation.
Identifiants
pubmed: 38110475
doi: 10.1038/s41557-023-01379-8
pii: 10.1038/s41557-023-01379-8
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM137606
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM132825
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM118062
Pays : United States
Organisme : NIBIB NIH HHS
ID : R01 EB031172
Pays : United States
Organisme : NIBIB NIH HHS
ID : R01 EB027793
Pays : United States
Informations de copyright
© 2023. The Author(s), under exclusive licence to Springer Nature Limited.
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