Trisubstituted purine inhibitors of PDGFRα and their antileukemic activity in the human eosinophilic cell line EOL-1
Language English Country Great Britain, England Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
29089259
DOI
10.1016/j.bmc.2017.10.032
PII: S0968-0896(17)31763-7
Knihovny.cz E-resources
- MeSH
- Protein Kinase Inhibitors chemical synthesis chemistry pharmacology MeSH
- Humans MeSH
- Molecular Structure MeSH
- Tumor Cells, Cultured MeSH
- Cell Proliferation drug effects MeSH
- Antineoplastic Agents chemical synthesis chemistry pharmacology MeSH
- Purines chemical synthesis chemistry pharmacology MeSH
- Receptor, Platelet-Derived Growth Factor alpha antagonists & inhibitors genetics metabolism MeSH
- Drug Screening Assays, Antitumor MeSH
- Dose-Response Relationship, Drug MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Protein Kinase Inhibitors MeSH
- Antineoplastic Agents MeSH
- purine MeSH Browser
- Purines MeSH
- Receptor, Platelet-Derived Growth Factor alpha MeSH
Inhibition of protein kinases is a validated concept for pharmacological intervention in cancers. Many kinase inhibitors have been approved for clinical use, but their practical application is often limited. Here, we describe a collection of 23 novel 2,6,9-trisubstituted purine derivatives with nanomolar inhibitory activities against PDGFRα, a receptor tyrosine kinase often found constitutively activated in various tumours. The compounds demonstrated strong and selective cytotoxicity in the human eosinophilic leukemia cell line EOL-1, whereas several other cell lines were substantially less sensitive. The cytotoxicity in EOL-1, which is known to express the FIP1L1-PDGFRA fusion gene encoding an oncogenic kinase, correlated significantly with PDGFRα inhibition. EOL-1 cells treated with the compounds also exhibited dose-dependent inhibition of PDGFRα autophosphorylation and suppression of its downstream signaling pathways with concomitant G1 phase arrest, confirming the proposed mechanism of action. Our results show that substituted purines can be used as platforms for preparing tyrosine kinase inhibitors with specific activity towards eosinophilic leukemia.
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