3D-QSAR Design of New Bcr-Abl Inhibitors Based on Purine Scaffold and Cytotoxicity Studies on CML Cell Lines Sensitive and Resistant to Imatinib

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61389030%3A_____%2F25%3A00637820" target="_blank" >RIV/61389030:_____/25:00637820 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/61989592:15310/25:73631115

Výsledek na webu

<a href="https://doi.org/10.3390/ph18060925" target="_blank" >https://doi.org/10.3390/ph18060925</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.3390/ph18060925" target="_blank" >10.3390/ph18060925</a>

Jazyk výsledku

angličtina

Název v původním jazyce

3D-QSAR Design of New Bcr-Abl Inhibitors Based on Purine Scaffold and Cytotoxicity Studies on CML Cell Lines Sensitive and Resistant to Imatinib

Popis výsledku v původním jazyce

Bcr-Abl inhibitors such as imatinib have been used to treat chronic myeloid leukemia (CML). However, the efficacy of these drugs has diminished due to mutations in the kinase domain, notably the T315I mutation. Therefore, in this study, new purine derivatives were designed as Bcr-Abl inhibitors based on 3D-QSAR studies. nMethods: nA database of 58 purines that inhibit Bcr-Abl was used to construct 3D-QSAR models. Using chemical information from these models, a small group of new purines was designed, synthesized, and evaluated in Bcr-Abl. Viability assays were conducted on imatinib-sensitive CML cells (K562 and KCL22) and imatinib-resistant cells (KCL22-B8). In silico analyses were performed to confirm the results. Results: Seven purines were easily synthesized (7a-g). Compounds 7a and 7c demonstrated the highest inhibition activity on Bcr-Abl (IC50 = 0.13 and 0.19 mu M), surpassing the potency of imatinib (IC50 = 0.33 mu M). 7c exhibited the highest potency, with GI(50) = 0.30 mu M on K562 cells and 1.54 mu M on KCL22 cells. The GI(50) values obtained for non-neoplastic HEK293T cells indicated that 7c was less toxic than imatinib. Interestingly, KCL22-B8 cells (expressing Bcr-Abl(T315I)) showed greater sensitivity to 7e and 7f than to imatinib (GI(50) = 13.80 and 15.43 vs. >20 mu M, respectively). In silico analyses, including docking and molecular dynamics studies of Bcr-Abl(T315I), were conducted to elucidate the enhanced potency of 7e and 7f. Thus, this study provides in silico models to identify novel inhibitors that target a kinase of significance in CML.

Název v anglickém jazyce

3D-QSAR Design of New Bcr-Abl Inhibitors Based on Purine Scaffold and Cytotoxicity Studies on CML Cell Lines Sensitive and Resistant to Imatinib

Popis výsledku anglicky

Bcr-Abl inhibitors such as imatinib have been used to treat chronic myeloid leukemia (CML). However, the efficacy of these drugs has diminished due to mutations in the kinase domain, notably the T315I mutation. Therefore, in this study, new purine derivatives were designed as Bcr-Abl inhibitors based on 3D-QSAR studies. nMethods: nA database of 58 purines that inhibit Bcr-Abl was used to construct 3D-QSAR models. Using chemical information from these models, a small group of new purines was designed, synthesized, and evaluated in Bcr-Abl. Viability assays were conducted on imatinib-sensitive CML cells (K562 and KCL22) and imatinib-resistant cells (KCL22-B8). In silico analyses were performed to confirm the results. Results: Seven purines were easily synthesized (7a-g). Compounds 7a and 7c demonstrated the highest inhibition activity on Bcr-Abl (IC50 = 0.13 and 0.19 mu M), surpassing the potency of imatinib (IC50 = 0.33 mu M). 7c exhibited the highest potency, with GI(50) = 0.30 mu M on K562 cells and 1.54 mu M on KCL22 cells. The GI(50) values obtained for non-neoplastic HEK293T cells indicated that 7c was less toxic than imatinib. Interestingly, KCL22-B8 cells (expressing Bcr-Abl(T315I)) showed greater sensitivity to 7e and 7f than to imatinib (GI(50) = 13.80 and 15.43 vs. >20 mu M, respectively). In silico analyses, including docking and molecular dynamics studies of Bcr-Abl(T315I), were conducted to elucidate the enhanced potency of 7e and 7f. Thus, this study provides in silico models to identify novel inhibitors that target a kinase of significance in CML.

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

2025

Kód důvěrnosti údajů

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

Název periodika

Pharmaceuticals

ISSN

1424-8247

e-ISSN

1424-8247

Svazek periodika

18

Číslo periodika v rámci svazku

6

Stát vydavatele periodika

CH - Švýcarská konfederace

Počet stran výsledku

27

Strana od-do

925

Kód UT WoS článku

001515636300001

EID výsledku v databázi Scopus

2-s2.0-105009003306