PUBLICATION
Potent Suppressive Effects of 1-Piperidinylimidazole Based Novel P2X7 Receptor Antagonists on Cancer Cell Migration and Invasion
- Authors
- Park, J.H., Williams, D.R., Lee, J.H., Lee, S.D., Lee, J.H., Ko, H., Lee, G.E., Kim, S., Lee, J.M., Abdelrahman, A., Müller, C.E., Jung, D.W., Kim, Y.C.
- ID
- ZDB-PUB-160720-4
- Date
- 2016
- Source
- Journal of medicinal chemistry 59(16): 7410-30 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Animals
- Antineoplastic Agents/chemical synthesis
- Antineoplastic Agents/chemistry
- Antineoplastic Agents/pharmacology*
- Cell Movement/drug effects
- Cell Proliferation/drug effects
- Cell Survival/drug effects
- Dose-Response Relationship, Drug
- Drug Screening Assays, Antitumor
- Female
- HEK293 Cells
- Humans
- Imidazoles/chemical synthesis
- Imidazoles/chemistry
- Imidazoles/pharmacology*
- Mammary Neoplasms, Experimental/drug therapy
- Mammary Neoplasms, Experimental/pathology
- Molecular Structure
- Piperidines/chemical synthesis
- Piperidines/chemistry
- Piperidines/pharmacology*
- Structure-Activity Relationship
- Tumor Cells, Cultured
- Zebrafish
- PubMed
- 27427902 Full text @ J. Med. Chem.
Citation
Park, J.H., Williams, D.R., Lee, J.H., Lee, S.D., Lee, J.H., Ko, H., Lee, G.E., Kim, S., Lee, J.M., Abdelrahman, A., Müller, C.E., Jung, D.W., Kim, Y.C. (2016) Potent Suppressive Effects of 1-Piperidinylimidazole Based Novel P2X7 Receptor Antagonists on Cancer Cell Migration and Invasion. Journal of medicinal chemistry. 59(16):7410-30.
Abstract
The P2X7 receptor (P2X7R) has been reported as a key mediator in inflammatory processes and cancer invasion/metastasis. In this study, we report the discovery of novel P2X7R antagonists and their functional activities as potential anti-metastatic agents. Modifications of the hydantoin core-skeleton and the side chain substituents of P2X7R antagonist, 7 were performed. The structure-activity relationships (SAR) and optimization demonstrated the importance of the sulfonyl group at the R1 position, and the substituted position and overall size of R2 for P2X7R antagonism. The optimized novel analogs displayed potent P2X7 receptor antagonism (IC50 = 0.11-112 nM) along with significant suppressive effects on IL-1β release (IC50 = 0.32-210 nM). Moreover, representative antagonists (12g, 13k, and 17d) with imidazole and uracil core skeletons significantly inhibited the invasion of MDA-MB-231 triple negative breast cancer cells and cancer cell migration in a zebrafish xenograft model, suggesting potential therapeutic application of these novel P2X7 antagonists to block metastatic cancer.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping