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

Result code in 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>

Alternative codes found

RIV/61989592:15310/25:73631115

Result on the web

<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>

Result language

angličtina

Original language name

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

Original language description

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.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

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OECD FORD branch

30205 - Hematology

Project

Result was created during the realization of more than one project. More information in the Projects tab.

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2025

Confidentiality

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

Name of the periodical

Pharmaceuticals

ISSN

1424-8247

e-ISSN

1424-8247

Volume of the periodical

18

Issue of the periodical within the volume

6

Country of publishing house

CH - SWITZERLAND

Number of pages

27

Pages from-to

925

UT code for WoS article

001515636300001

EID of the result in the Scopus database

2-s2.0-105009003306