On the correlation of cereblon binding, fluorination and antiangiogenic properties of immunomodulatory drugs.
Adaptor Proteins, Signal Transducing
/ metabolism
Angiogenesis Inhibitors
/ chemistry
Animals
Aorta
/ drug effects
Drug Evaluation, Preclinical
Halogenation
Human Umbilical Vein Endothelial Cells
Humans
Immunologic Factors
/ chemistry
Male
Rats, Sprague-Dawley
Structure-Activity Relationship
Thalidomide
/ analogs & derivatives
Ubiquitin-Protein Ligases
/ metabolism
CRBN
Cancer therapy
IMiDs
MST
Microscale thermophoresis
Journal
Biochemical and biophysical research communications
ISSN: 1090-2104
Titre abrégé: Biochem Biophys Res Commun
Pays: United States
ID NLM: 0372516
Informations de publication
Date de publication:
01 01 2021
01 01 2021
Historique:
received:
26
11
2020
accepted:
27
11
2020
pubmed:
15
12
2020
medline:
14
4
2021
entrez:
14
12
2020
Statut:
ppublish
Résumé
Cereblon (CRBN), the substrate receptor of an E3 ubiquitin ligase complex, is a target of thalidomide and thalidomide-derived immunomodulatory drugs (IMiDs). The binding of these IMiDs to CRBN alters the substrate specificity of the ligase, thereby mediating multiple effects that are exploited in cancer therapy. However, to date, it is not clear which other possible targets might be involved in the efficacy of IMiDs. One especially prominent effect of a number of thalidomide analogs is their ability to inhibit angiogenesis, which is typically enhanced in fluorinated analogs. So far, the involvement of CRBN in antiangiogenic effects is under debate. Here, starting from a systematic set of thalidomide analogs and employing a quantitative in vitro CRBN-binding assay, we study the correlation of fluorination, CRBN binding and antiangiogenic effects. We clearly identify fluorination to correlate both with CRBN binding affinity and with antiangiogenic effects, but do not find a correlation between the latter two phenomena, indicating that the main target for the antiangiogenic effects of thalidomide analogs still remains to be identified.
Identifiants
pubmed: 33310190
pii: S0006-291X(20)32161-6
doi: 10.1016/j.bbrc.2020.11.117
pmc: PMC7815984
mid: NIHMS1654296
pii:
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
Angiogenesis Inhibitors
0
CRBN protein, human
0
Immunologic Factors
0
Thalidomide
4Z8R6ORS6L
Ubiquitin-Protein Ligases
EC 2.3.2.27
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
67-72Subventions
Organisme : Intramural NIH HHS
ID : ZIA SC006538
Pays : United States
Informations de copyright
Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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