Design, synthesis, and biological evaluation of novel azaspirooxindolinone derivatives as potent inhibitors of ITK and BTK-dependent cancers

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61989592%3A15640%2F25%3A73630462" target="_blank" >RIV/61989592:15640/25:73630462 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00098892:_____/25:10159169 RIV/61989592:15110/25:73630462

Výsledek na webu

<a href="https://www.sciencedirect.com/science/article/pii/S0968089625000574?ref=pdf_download&fr=RR-2&rr=9255ba02da81f9a0" target="_blank" >https://www.sciencedirect.com/science/article/pii/S0968089625000574?ref=pdf_download&fr=RR-2&rr=9255ba02da81f9a0</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.bmc.2025.118116" target="_blank" >10.1016/j.bmc.2025.118116</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Design, synthesis, and biological evaluation of novel azaspirooxindolinone derivatives as potent inhibitors of ITK and BTK-dependent cancers

Popis výsledku v původním jazyce

Interleukin-2-inducible T-cell kinase (ITK) and Bruton&apos;s tyrosine kinase (BTK) are two important members of the Tec family with crucial roles in immune system function. Deregulation in ITK and BTK activity is linked to several hematological malignancies, making them key targets for cancer immunotherapy. In this study, we synthesized a series of azaspirooxindolinone derivatives and evaluated their cytotoxic activity against ITK/BTK-negative and positive cancer cell lines, followed by enzymatic inhibition studies to assess the ITK/BTK kinase selectivity of two hit compounds. Several compounds demonstrated selective cytotoxicity against ITK- or BTK-expressing cells. Compound 3d exhibited high cytotoxicity in ITK-positive Jurkat (IC50 = 3.58 mu M) and BTK-positive Ramos (IC50 = 3.06 mu M) cells, while compound 3j showed strong cytotoxicity in Ramos (IC50 = 1.38 mu M) and Jurkat (IC50 = 4.16 mu M) cells. Compounds 3a and 3e were selectively cytotoxic in Jurkat cells (IC50 = 9.36 mu M and 10.85 mu M, respectively), while compounds 3f and 3g were highly cytotoxic in Ramos cells (IC50 = 1.82 mu M and 1.42 mu M, respectively). None of the active compounds exhibited cytotoxicity in non-cancer cell lines (IC50 &gt; 50 mu M), demonstrating their selectivity for malignant cells. Enzyme inhibition assay showed that 3d is a selective ITK inhibitor (IC50 = 0.91 mu M) with no detectable BTK inhibition, aligning with its strong activity in ITK-positive cells. In contrast, compound 3j did not inhibit ITK or BTK enzymatically, suggesting an alternative mechanism of action. These findings highlight 3d as a promising ITK inhibitor and warrant further investigation to elucidate its mechanism of action.

Název v anglickém jazyce

Design, synthesis, and biological evaluation of novel azaspirooxindolinone derivatives as potent inhibitors of ITK and BTK-dependent cancers

Popis výsledku anglicky

Interleukin-2-inducible T-cell kinase (ITK) and Bruton&apos;s tyrosine kinase (BTK) are two important members of the Tec family with crucial roles in immune system function. Deregulation in ITK and BTK activity is linked to several hematological malignancies, making them key targets for cancer immunotherapy. In this study, we synthesized a series of azaspirooxindolinone derivatives and evaluated their cytotoxic activity against ITK/BTK-negative and positive cancer cell lines, followed by enzymatic inhibition studies to assess the ITK/BTK kinase selectivity of two hit compounds. Several compounds demonstrated selective cytotoxicity against ITK- or BTK-expressing cells. Compound 3d exhibited high cytotoxicity in ITK-positive Jurkat (IC50 = 3.58 mu M) and BTK-positive Ramos (IC50 = 3.06 mu M) cells, while compound 3j showed strong cytotoxicity in Ramos (IC50 = 1.38 mu M) and Jurkat (IC50 = 4.16 mu M) cells. Compounds 3a and 3e were selectively cytotoxic in Jurkat cells (IC50 = 9.36 mu M and 10.85 mu M, respectively), while compounds 3f and 3g were highly cytotoxic in Ramos cells (IC50 = 1.82 mu M and 1.42 mu M, respectively). None of the active compounds exhibited cytotoxicity in non-cancer cell lines (IC50 &gt; 50 mu M), demonstrating their selectivity for malignant cells. Enzyme inhibition assay showed that 3d is a selective ITK inhibitor (IC50 = 0.91 mu M) with no detectable BTK inhibition, aligning with its strong activity in ITK-positive cells. In contrast, compound 3j did not inhibit ITK or BTK enzymatically, suggesting an alternative mechanism of action. These findings highlight 3d as a promising ITK inhibitor and warrant further investigation to elucidate its mechanism of action.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

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

Bioorganic and Medicinal Chemistry

ISSN

0968-0896

e-ISSN

1464-3391

Svazek periodika

121

Číslo periodika v rámci svazku

15.4.2025

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

9

Strana od-do

nestránkováno

Kód UT WoS článku

001436890700001

EID výsledku v databázi Scopus

2-s2.0-85218503979