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

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61389030%3A_____%2F17%3A00482957" target="_blank" >RIV/61389030:_____/17:00482957 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/61989592:15310/17:73584379

Výsledek na webu

<a href="http://dx.doi.org/10.1016/j.bmc.2017.10.032" target="_blank" >http://dx.doi.org/10.1016/j.bmc.2017.10.032</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.bmc.2017.10.032" target="_blank" >10.1016/j.bmc.2017.10.032</a>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30205 - Hematology

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2017

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Bioorganic & Medicinal Chemistry

ISSN

0968-0896

e-ISSN

—

Svazek periodika

25

Číslo periodika v rámci svazku

24

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

13

Strana od-do

6523-6535

Kód UT WoS článku

000415984900027

EID výsledku v databázi Scopus

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