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

0512138 - ÚEB 2020 RIV FR eng J - Journal Article
Řezníčková, Eva - Gucký, Tomáš - Kováčová, Veronika - Ajani, Haresh - Jorda, Radek - Kryštof, Vladimír
Activity of 2,6,9-trisubstituted purines as potent PDGFRα kinase inhibitors with antileukaemic activity.
European Journal of Medicinal Chemistry. Roč. 182, Nov 15 (2019), č. článku 111663. ISSN 0223-5234. E-ISSN 1768-3254
Institutional support: RVO:61389030 ; RVO:61388963
Keywords : Acute myeloid leukaemia * Eosinophilic leukaemia * Kinase inhibitor * PDGFRα
OECD category: Hematology
Impact factor: 5.573, year: 2019
Method of publishing: Limited access
http://dx.doi.org/10.1016/j.ejmech.2019.111663

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.
Permanent Link: http://hdl.handle.net/11104/0302348