2. Academic Validation
  3. Activity of 2,6,9-trisubstituted purines as potent PDGFRα kinase inhibitors with antileukaemic activity

Activity of 2,6,9-trisubstituted purines as potent PDGFRα kinase inhibitors with antileukaemic activity

  • Eur J Med Chem. 2019 Nov 15:182:111663. doi: 10.1016/j.ejmech.2019.111663.
Eva Řezníčková 1,  Tomáš Gucký 1,  Veronika Kováčová 1,  Haresh Ajani 2,  Radek Jorda 1,  Vladimír Kryštof 3
Affiliations

Affiliations

  • 1 Laboratory of Growth Regulators, Palacký University and Institute of Experimental Botany, The Czech Academy of Sciences, Šlechtitelů 27, 783 71 Olomouc, Czech Republic.
  • 2 Institute of Organic Chemistry and Biochemistry, The Czech Academy of Sciences, Flemingovo nám. 2, 166 10 Prague 6, Czech Republic.
  • 3 Laboratory of Growth Regulators, Palacký University and Institute of Experimental Botany, The Czech Academy of Sciences, Šlechtitelů 27, 783 71 Olomouc, Czech Republic. Electronic address: vladimir.krystof@upol.cz.
PMID: 31514019 DOI: 10.1016/j.ejmech.2019.111663
Abstract

Receptor tyrosine kinase PDGFRα is often constitutively activated in various tumours and is regarded as a drug target. Here, we present a collection of 2,6,9-trisubstituted purines with nanomolar potency against PDGFRα and strong and selective cytotoxicity in the human eosinophilic leukaemia cell line EOL-1 that expresses the FIP1L1-PDGFRA oncogene. In treated EOL-1 cells, the example compound 14q inhibited the autophosphorylation of PDGFRα and the phosphorylation of STAT3 and ERK1/2. Interestingly, we observed pronounced and even increased effects of 14q on PDGFRα and some of its downstream signalling pathways after drug washout. In accordance with suppressed PDGFRα signalling, treated cells were arrested in the G1 phase of the cell cycle and eventually underwent Apoptosis. Our results show that substituted purines can be used as specific modulators of eosinophilic leukaemia.

Keywords

Acute myeloid leukaemia; Eosinophilic leukaemia; Kinase inhibitor; PDGFRα.

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