Trisubstituted purine inhibitors of PDGFR alpha and their antileukemic activity in the human eosinophilic cell line EOL-1

0482957 - ÚEB 2018 RIV GB eng J - Journal Article
Malínková, Veronika - Řezníčková, Eva - Jorda, Radek - Gucký, T. - Kryštof, Vladimír
Trisubstituted purine inhibitors of PDGFR alpha and their antileukemic activity in the human eosinophilic cell line EOL-1.
Bioorganic & Medicinal Chemistry. Roč. 25, č. 24 (2017), s. 6523-6535. ISSN 0968-0896. E-ISSN 1464-3391
R&D Projects: GA MŠMT(CZ) LO1204
Institutional support: RVO:61389030
Keywords : dependent kinase inhibitors * src tyrosine kinase * 2,6,9-trisubstituted purines * therapeutic target * potent inhibitor * imatinib * leukemia * mutations * mutant * domain
OECD category: Hematology
Impact factor: 2.881, year: 2017

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 PDGFR alpha, 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-PDGFR alpha fusion gene encoding an oncogenic kinase, correlated significantly with PDGFR alpha inhibition. EOL-1 cells treated with the compounds also exhibited dose-dependent inhibition of PDGFR alpha 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.
Permanent Link: http://hdl.handle.net/11104/0278331