IODVA1, a guanidinobenzimidazole derivative, targets Rac activity and Ras-driven cancer models.
Animals
Antineoplastic Agents
/ chemical synthesis
Benzimidazoles
/ chemical synthesis
Breast Neoplasms
/ drug therapy
Cell Proliferation
/ drug effects
Female
HEK293 Cells
Humans
Lung Neoplasms
/ drug therapy
MCF-7 Cells
Mice
Mice, Nude
NIH 3T3 Cells
Tumor Stem Cell Assay
Xenograft Model Antitumor Assays
ras Proteins
/ antagonists & inhibitors
Journal
PloS one
ISSN: 1932-6203
Titre abrégé: PLoS One
Pays: United States
ID NLM: 101285081
Informations de publication
Date de publication:
2020
2020
Historique:
received:
05
11
2019
accepted:
13
02
2020
entrez:
13
3
2020
pubmed:
13
3
2020
medline:
21
7
2020
Statut:
epublish
Résumé
We report the synthesis and preliminary characterization of IODVA1, a potent small molecule that is active in xenograft mouse models of Ras-driven lung and breast cancers. In an effort to inhibit oncogenic Ras signaling, we combined in silico screening with inhibition of proliferation and colony formation of Ras-driven cells. NSC124205 fulfilled all criteria. HPLC analysis revealed that NSC124205 was a mixture of at least three compounds, from which IODVA1 was determined to be the active component. IODVA1 decreased 2D and 3D cell proliferation, cell spreading and ruffle and lamellipodia formation through downregulation of Rac activity. IODVA1 significantly impaired xenograft tumor growth of Ras-driven cancer cells with no observable toxicity. Immuno-histochemistry analysis of tumor sections suggests that cell death occurs by increased apoptosis. Our data suggest that IODVA1 targets Rac signaling to induce death of Ras-transformed cells. Therefore, IODVA1 holds promise as an anti-tumor therapeutic agent.
Identifiants
pubmed: 32163428
doi: 10.1371/journal.pone.0229801
pii: PONE-D-19-30856
pmc: PMC7067412
doi:
Substances chimiques
Antineoplastic Agents
0
Benzimidazoles
0
ras Proteins
EC 3.6.5.2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0229801Subventions
Organisme : NCI NIH HHS
ID : R01 CA115611
Pays : United States
Organisme : NCI NIH HHS
ID : R37 CA218072
Pays : United States
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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