New Inhibitors of Bcr-Abl Based on 2,6,9-Trisubstituted Purine Scaffold Elicit Cytotoxicity in Chronic Myeloid Leukemia-Derived Cell Lines Sensitive and Resistant to TKIs

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61389030%3A_____%2F24%3A00599784" target="_blank" >RIV/61389030:_____/24:00599784 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/61989592:15310/24:73625019

Výsledek na webu

<a href="https://doi.org/10.3390/pharmaceutics16050649" target="_blank" >https://doi.org/10.3390/pharmaceutics16050649</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.3390/pharmaceutics16050649" target="_blank" >10.3390/pharmaceutics16050649</a>

Jazyk výsledku

angličtina

Název v původním jazyce

New Inhibitors of Bcr-Abl Based on 2,6,9-Trisubstituted Purine Scaffold Elicit Cytotoxicity in Chronic Myeloid Leukemia-Derived Cell Lines Sensitive and Resistant to TKIs

Popis výsledku v původním jazyce

Bcr-Abl is an oncoprotein with aberrant tyrosine kinase activity involved in the progression of chronic myeloid leukemia (CML) and has been targeted by inhibitors such as imatinib and nilotinib. However, despite their efficacy in the treatment of CML, a mechanism of resistance to these drugs associated with mutations in the kinase region has emerged. Therefore, in this work, we report the synthesis of 14 new 2,6,9-trisubstituted purines designed from our previous Bcr-Abl inhibitors. Here, we highlight 11b, which showed higher potency against Bcr-Abl (IC50 = 0.015 mu M) than imatinib and nilotinib and exerted the most potent antiproliferative properties on three CML cells harboring the Bcr-Abl rearrangement (GI(50) = 0.7-1.3 mu M). In addition, these purines were able to inhibit the growth of KCL22 cell lines expressing Bcr-Abl(T315I), Bcr-Abl(E255K), and Bcr-Abl(Y253H) point mutants in micromolar concentrations. Imatinib and nilotinib were ineffective in inhibiting the growth of KCL22 cells expressing Bcr-Abl(T315I) (GI(50) > 20 mu M) compared to 11b-f (GI(50) = 6.4-11.5 mu M). Molecular docking studies explained the structure-activity relationship of these purines in Bcr-Abl(WT) and Bcr-Abl(T315I). Finally, cell cycle cytometry assays and immunodetection showed that 11b arrested the cells in G1 phase, and that 11b downregulated the protein levels downstream of Bcr-Abl in these cells.

Název v anglickém jazyce

New Inhibitors of Bcr-Abl Based on 2,6,9-Trisubstituted Purine Scaffold Elicit Cytotoxicity in Chronic Myeloid Leukemia-Derived Cell Lines Sensitive and Resistant to TKIs

Popis výsledku anglicky

Bcr-Abl is an oncoprotein with aberrant tyrosine kinase activity involved in the progression of chronic myeloid leukemia (CML) and has been targeted by inhibitors such as imatinib and nilotinib. However, despite their efficacy in the treatment of CML, a mechanism of resistance to these drugs associated with mutations in the kinase region has emerged. Therefore, in this work, we report the synthesis of 14 new 2,6,9-trisubstituted purines designed from our previous Bcr-Abl inhibitors. Here, we highlight 11b, which showed higher potency against Bcr-Abl (IC50 = 0.015 mu M) than imatinib and nilotinib and exerted the most potent antiproliferative properties on three CML cells harboring the Bcr-Abl rearrangement (GI(50) = 0.7-1.3 mu M). In addition, these purines were able to inhibit the growth of KCL22 cell lines expressing Bcr-Abl(T315I), Bcr-Abl(E255K), and Bcr-Abl(Y253H) point mutants in micromolar concentrations. Imatinib and nilotinib were ineffective in inhibiting the growth of KCL22 cells expressing Bcr-Abl(T315I) (GI(50) > 20 mu M) compared to 11b-f (GI(50) = 6.4-11.5 mu M). Molecular docking studies explained the structure-activity relationship of these purines in Bcr-Abl(WT) and Bcr-Abl(T315I). Finally, cell cycle cytometry assays and immunodetection showed that 11b arrested the cells in G1 phase, and that 11b downregulated the protein levels downstream of Bcr-Abl in these cells.

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

2024

Kód důvěrnosti údajů

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

Název periodika

Pharmaceutics

ISSN

1999-4923

e-ISSN

1999-4923

Svazek periodika

16

Číslo periodika v rámci svazku

5

Stát vydavatele periodika

CH - Švýcarská konfederace

Počet stran výsledku

23

Strana od-do

649

Kód UT WoS článku

001233653100001

EID výsledku v databázi Scopus

2-s2.0-85194263187