Design, synthesis, and biological evaluation of novel 3-oxo-2,3-dihydropyridazine derivatives as interleukin-2-inducible T-cell kinase (ITK) inhibitors
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00098892%3A_____%2F25%3A10159605" target="_blank" >RIV/00098892:_____/25:10159605 - isvavai.cz</a>
Result on the web
<a href="https://pubs.rsc.org/en/content/articlelanding/2025/ra/d5ra06565h" target="_blank" >https://pubs.rsc.org/en/content/articlelanding/2025/ra/d5ra06565h</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1039/d5ra06565h" target="_blank" >10.1039/d5ra06565h</a>
Alternative languages
Result language
angličtina
Original language name
Design, synthesis, and biological evaluation of novel 3-oxo-2,3-dihydropyridazine derivatives as interleukin-2-inducible T-cell kinase (ITK) inhibitors
Original language description
This study reports the design, synthesis, and biological evaluation of a novel series of 3-oxo-2,3-dihydropyridazine derivatives, representing a previously unexplored scaffold for selective inhibition of interleukin-2-inducible T-cell kinase (ITK), with potential application in T-cell leukemia treatment. Cytotoxicity was assessed across a panel of ITK-expressing leukemia cell lines (Jurkat, CCRF-CEM), Bruton's tyrosine kinase (BTK)-positive lines (Ramos, K562), ITK/BTK-null cancer cells, and non-cancerous fibroblasts to determine therapeutic selectivity. Compound 9 emerged as the lead candidate, showing selective ITK inhibition in biochemical kinase assays (half-maximal inhibitory concentration, IC₅₀ = 0.87 µM) with no measurable BTK inhibition, moderate cytotoxicity in Jurkat cells (cellular IC₅₀ = 37.61 µM), and did not show measurable cytotoxicity in fibroblasts (IC₅₀ > 50 µM). In contrast, 22 exhibited greater potency in both kinase [IC₅₀ (ITK) = 0.19 µM] and cytotoxicity assay [IC₅₀ (Jurkat) = 11.17 µM], but showed partial BTK inhibition, indicating reduced selectivity. Structure–activity relationship analysis indicated that the 3,5-difluorophenyl and furan-2-ylmethyl groups in 22 contributed to potency, while the 3-fluorophenyl group in 9 was associated with improved selectivity. Importantly, western blot analysis confirmed that 9 reduced phosphorylation of ITK (Tyr551/Tyr511) and downstream extracellular signal-regulated kinase 1/2 (ERK1/2) (Thr202/Tyr204) in phytohemagglutinin-stimulated Jurkat cells, supporting on-target inhibition of ITK signaling. These results position 9 as a selective ITK inhibitor with a favorable therapeutic index, establishing a foundation for further optimization and preclinical development.
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
30107 - Medicinal chemistry
Result continuities
Project
<a href="/en/project/EH22_008%2F0004644" target="_blank" >EH22_008/0004644: Saving lives through research in early cancer detection and prevention: Molecular, genomic and societal factors</a><br>
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)
Others
Publication year
2025
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
RSC Advances
ISSN
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e-ISSN
2046-2069
Volume of the periodical
15
Issue of the periodical within the volume
55
Country of publishing house
GB - UNITED KINGDOM
Number of pages
22
Pages from-to
47565-47586
UT code for WoS article
001630616700001
EID of the result in the Scopus database
2-s2.0-105024321785