Chlorinated benzothiadiazines inhibit angiogenesis through suppression of VEGFR2 phosphorylation.
Angiogenesis Inhibitors
/ pharmacology
Benzothiadiazines
/ metabolism
Cell Movement
Cell Proliferation
Human Umbilical Vein Endothelial Cells
/ metabolism
Humans
Neovascularization, Pathologic
/ drug therapy
Phosphorylation
Protein-Tyrosine Kinases
/ metabolism
Vascular Endothelial Growth Factor A
/ metabolism
Vascular Endothelial Growth Factor Receptor-2
Angiogenesis
Kinase inhibitor
Mechanism of action
VEGFR2
Journal
Bioorganic & medicinal chemistry
ISSN: 1464-3391
Titre abrégé: Bioorg Med Chem
Pays: England
ID NLM: 9413298
Informations de publication
Date de publication:
01 08 2022
01 08 2022
Historique:
received:
05
03
2022
revised:
28
04
2022
accepted:
04
05
2022
pubmed:
1
6
2022
medline:
9
6
2022
entrez:
31
5
2022
Statut:
ppublish
Résumé
Angiogenesis inhibitors are a critical pharmacological tool for the treatment of solid tumors. Suppressing vascular permeability leads to inhibition of tumor growth, invasion, and metastatic potential by blocking the supply of oxygen and nutrients. Disruption of the vascular endothelial growth factor (VEGF) signaling pathway is a validated target for the design of antiangiogenic agents. Several VEGFR2 inhibitors have been clinically approved over the past years. Structural analysis of these clinical VEGFR2 inhibitors highlighted key functional group overlap with the benzothiadiazine core contained in a library of in-house compounds. Herein we ascribe anti-angiogenic activity to a series of chlorinated benzothiadiazines. Selected compounds show significant activity to completely ameliorate VEGF-induced endothelial cell proliferation by suppression of VEGFR2 phosphorylation. The scaffold is devoid of activity to inhibit carbonic anhydrases and generally lacks cytotoxicity across a range of cancer and non-malignant cell lines. Assay of activity at 468 kinases shows remarkable selectivity with only four kinases inhibited > 65% at 10 µM concentration, and with significant activity to inhibit TNK2/ACK1 and PKRD2 by > 90%. All four identified kinase targets are known modulators of angiogenesis, thus highlighting compound 17b as a novel angiogenesis inhibitor for further development.
Identifiants
pubmed: 35635929
pii: S0968-0896(22)00197-3
doi: 10.1016/j.bmc.2022.116805
pmc: PMC9888588
mid: NIHMS1865054
pii:
doi:
Substances chimiques
Angiogenesis Inhibitors
0
Benzothiadiazines
0
Vascular Endothelial Growth Factor A
0
Protein-Tyrosine Kinases
EC 2.7.10.1
Vascular Endothelial Growth Factor Receptor-2
EC 2.7.10.1
TNK2 protein, human
EC 2.7.10.2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
116805Subventions
Organisme : NCI NIH HHS
ID : P30 CA036727
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA226436
Pays : United States
Informations de copyright
Copyright © 2022 Elsevier Ltd. All rights reserved.
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