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

摘要

Receptor tyrosine kinase PDGFR alpha 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 PDGFR alpha 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 PDGFR alpha and the phosphorylation of STAT3 and ERK1/2. Interestingly, we observed pronounced and even increased effects of 14q on PDGFR alpha and some of its downstream signalling pathways after drug washout. In accordance with suppressed PDGFR alpha 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. (C) 2019 Elsevier Masson SAS. All rights reserved.