Design, synthesis, and biological evaluation of novel 3-oxo-2,3-dihydropyridazine derivatives as interleukin-2-inducible T-cell kinase (ITK) inhibitors

Kód výsledku v 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>

Výsledek na webu

<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>

Jazyk výsledku

angličtina

Název v původním jazyce

Design, synthesis, and biological evaluation of novel 3-oxo-2,3-dihydropyridazine derivatives as interleukin-2-inducible T-cell kinase (ITK) inhibitors

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

Design, synthesis, and biological evaluation of novel 3-oxo-2,3-dihydropyridazine derivatives as interleukin-2-inducible T-cell kinase (ITK) inhibitors

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30107 - Medicinal chemistry

Projekt

<a href="/cs/project/EH22_008%2F0004644" target="_blank" >EH22_008/0004644: Záchrana životů prostřednictvím výzkumu v oblasti včasné detekce a prevence rakoviny: Molekulární, genomické a sociální faktory</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2025

Kód důvěrnosti údajů

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

Název periodika

RSC Advances

ISSN

—

e-ISSN

2046-2069

Svazek periodika

15

Číslo periodika v rámci svazku

55

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

22

Strana od-do

47565-47586

Kód UT WoS článku

001630616700001

EID výsledku v databázi Scopus

2-s2.0-105024321785