Nutlin-3a-aa: Improving the Bioactivity of a p53/MDM2 Interaction Inhibitor by Introducing a Solvent-Exposed Methylene Group.
biological activity
drug design
inhibitors
protein structures
protein-protein interactions
Journal
Chembiochem : a European journal of chemical biology
ISSN: 1439-7633
Titre abrégé: Chembiochem
Pays: Germany
ID NLM: 100937360
Informations de publication
Date de publication:
14 03 2023
14 03 2023
Historique:
received:
04
01
2023
pubmed:
6
1
2023
medline:
17
3
2023
entrez:
5
1
2023
Statut:
ppublish
Résumé
Nutlin-3a is a reversible inhibitor of the p53/MDM2 interaction. We have synthesized the derivative Nutlin-3a-aa bearing an additional exocyclic methylene group in the piperazinone moiety. Nutlin-3a-aa is more active than Nutlin-3a against purified wild-type MDM2, and is more effective at increasing p53 levels and releasing transcription of p53 target genes from MDM2-induced repression. X-ray analysis of wild-type MDM2-bound Nutlin-3a-aa indicated that the orientation of its modified piperazinone ring was altered in comparison to the piperazinone ring of MDM2-bound Nutlin-3a, with the exocyclic methylene group of Nutlin-3a-aa pointing away from the protein surface. Our data point to the introduction of exocyclic methylene groups as a useful approach by which to tailor the conformation of bioactive molecules for improved biological activity.
Identifiants
pubmed: 36602436
doi: 10.1002/cbic.202300006
doi:
Substances chimiques
Tumor Suppressor Protein p53
0
nutlin 3
53IA0V845C
Proto-Oncogene Proteins c-mdm2
EC 2.3.2.27
Antineoplastic Agents
0
Imidazoles
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e202300006Informations de copyright
© 2023 The Authors. ChemBioChem published by Wiley-VCH GmbH.
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