PUBLICATION
Design, synthesis, and biological evaluation of 2,4-diamino pyrimidine derivatives as potent FAK inhibitors with anti-cancer and anti-angiogenesis activities
- Authors
- Wang, S., Zhang, R.H., Zhang, H., Wang, Y.C., Yang, D., Zhao, Y.L., Yan, G.Y., Xu, G.B., Guan, H.Y., Zhou, Y.H., Cui, D.B., Liu, T., Li, Y.J., Liao, S.G., Zhou, M.
- ID
- ZDB-PUB-210608-7
- Date
- 2021
- Source
- European Journal of Medicinal Chemistry 222: 113573 (Journal)
- Registered Authors
- Zhou, Yan-Hua
- Keywords
- Anti-angiogenesis, Antitumor, DAPY, FAK inhibitor, Structure-activity relationship
- MeSH Terms
-
- Angiogenesis Inhibitors/chemical synthesis
- Angiogenesis Inhibitors/chemistry
- Angiogenesis Inhibitors/pharmacology*
- Antineoplastic Agents/chemical synthesis
- Antineoplastic Agents/chemistry
- Antineoplastic Agents/pharmacology*
- Cell Proliferation/drug effects
- Cells, Cultured
- Dose-Response Relationship, Drug
- Drug Design*
- Drug Screening Assays, Antitumor
- Focal Adhesion Kinase 1/antagonists & inhibitors*
- Focal Adhesion Kinase 1/metabolism
- Humans
- Molecular Structure
- Neovascularization, Pathologic/drug therapy*
- Neovascularization, Pathologic/metabolism
- Neovascularization, Pathologic/pathology
- Protein Kinase Inhibitors/chemical synthesis
- Protein Kinase Inhibitors/chemistry
- Protein Kinase Inhibitors/pharmacology*
- Pyrimidines/chemical synthesis
- Pyrimidines/chemistry
- Pyrimidines/pharmacology*
- Structure-Activity Relationship
- PubMed
- 34091209 Full text @ Eur. J. Med. Chem.
Citation
Wang, S., Zhang, R.H., Zhang, H., Wang, Y.C., Yang, D., Zhao, Y.L., Yan, G.Y., Xu, G.B., Guan, H.Y., Zhou, Y.H., Cui, D.B., Liu, T., Li, Y.J., Liao, S.G., Zhou, M. (2021) Design, synthesis, and biological evaluation of 2,4-diamino pyrimidine derivatives as potent FAK inhibitors with anti-cancer and anti-angiogenesis activities. European Journal of Medicinal Chemistry. 222:113573.
Abstract
A series of 2,4-diamino pyrimidine (DAPY) derivatives were designed, synthesized, and evaluated as inhibitors of focal adhesion kinase (FAK) with antitumor and anti-angiogenesis activities. Most compounds effectively suppressed the enzymatic activities of FAK, and the IC50s of 11b and 12f were 2.75 and 1.87 nM, respectively. 11b and 12f exhibited strong antiproliferative effects against seven human cancer cells, with IC50 values against two FAK-overexpressing pancreatic cancer cells (PANC-1 and BxPC-3) of 0.98 μM, 0.55 μM, and 0.11 μM, 0.15 μM, respectively. Moreover, 11b and 12f obviously suppressed the colony formation, migration, and invasion of PANC-1 cells in a dose-dependent manner. Meanwhile, these two compounds could induce the apoptosis of PANC-1 cells and arrest the cell cycle in G2/M phase according to the flow cytometry assay. Western blot revealed that 11b and 12f effectively inhibited the FAK/PI3K/Akt signal pathway and significantly decreased the expression of cyclin D1 and Bcl-2. In addition, compounds 11b and 12f potently inhibited the antiproliferative of HUVECs and obviously altered the cell morphology. 11b and 12f also significantly inhibited the migration, tube formation of HUVECs and severely impaired the angiogenesis in the zebrafish model. Overall, these results revealed the potential of compounds 11b and 12f as promising candidates for further preclinical studies.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping