Discovery of a Novel Pseudo-Natural Product Aurora Kinase Inhibitor Chemotype through Morphological Profiling.
Aurora kinase inhibitor
indole dearomatization
interrupted fischer indole
morphological profiling
pseudo‐natural products
Journal
Advanced science (Weinheim, Baden-Wurttemberg, Germany)
ISSN: 2198-3844
Titre abrégé: Adv Sci (Weinh)
Pays: Germany
ID NLM: 101664569
Informations de publication
Date de publication:
03 Apr 2024
03 Apr 2024
Historique:
revised:
20
02
2024
received:
29
11
2023
medline:
4
4
2024
pubmed:
4
4
2024
entrez:
3
4
2024
Statut:
aheadofprint
Résumé
The pseudo-natural product (pseudo-NP) concept aims to combine NP fragments in arrangements that are not accessible through known biosynthetic pathways. The resulting compounds retain the biological relevance of NPs but are not yet linked to bioactivities and may therefore be best evaluated by unbiased screening methods resulting in the identification of unexpected or unprecedented bioactivities. Herein, various NP fragments are combined with a tricyclic core connectivity via interrupted Fischer indole and indole dearomatization reactions to provide a collection of highly three-dimensional pseudo-NPs. Target hypothesis generation by morphological profiling via the cell painting assay guides the identification of an unprecedented chemotype for Aurora kinase inhibition with both its relatively highly 3D structure and its physicochemical properties being very different from known inhibitors. Biochemical and cell biological characterization indicate that the phenotype identified by the cell painting assay corresponds to the inhibition of Aurora kinase B.
Identifiants
pubmed: 38569218
doi: 10.1002/advs.202309202
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e2309202Subventions
Organisme : European Union
ID : EFRE-0200481
Organisme : Innovative Medicines Initiative
ID : 115489
Organisme : Seventh Framework Programme
ID : FP7/2007-2013
Informations de copyright
© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.
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