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
The result's identifiers
Result code in 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>
Alternative codes found
RIV/61989592:15310/24:73625019
Result on the web
<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>
Alternative languages
Result language
angličtina
Original language name
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
Original language description
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.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - 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
Result continuities
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
Others
Publication year
2024
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Pharmaceutics
ISSN
1999-4923
e-ISSN
1999-4923
Volume of the periodical
16
Issue of the periodical within the volume
5
Country of publishing house
CH - SWITZERLAND
Number of pages
23
Pages from-to
649
UT code for WoS article
001233653100001
EID of the result in the Scopus database
2-s2.0-85194263187